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P13K delta-gamma anticancer agent

Posted in Biochemical pathways, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Drug Toxicity, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Gene Regulation and Evolution, Genetics & Innovations in Treatment, Genetics & Pharmaceutical, Genomic Expression, Hematology, Human Immune System in Health and in Disease, Innovations, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, Kinase, Lymphoma, Metabolism, Patents, Pharmaceutical Analytics, Pharmaceutical Drug Discovery, Pharmacologic toxicities, Proteins, Proteomics, Pyruvate Kinase, tagged oncotherapy, P13K delta/gamma isoforms, P13K selective targeting on December 10, 2015| Leave a Comment »

P13K delta-gamma anticancer agent

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

RP 6350, Rhizen Pharmaceuticals S.A. and Novartis tieup for Rhizen’s inhaled dual Pl3K-delta gamma inhibitor

by DR ANTHONY MELVIN CRASTO Ph.D

 

(A)           and                         (Al)                  and                (A2)

(S)-2-(l-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one (Compound A1 is RP 6350).

 

 

RP 6350, RP6350, RP-6350

(S)-2-(l-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one

mw 415

Rhizen Pharmaceuticals is developing RP-6530, a PI3K delta and gamma dual inhibitor, for the potential oral treatment of cancer and inflammation  In November 2013, a phase I trial in patients with hematologic malignancies was initiated in Italy ]\. In September 2015, a phase I/Ib study was initiated in the US, in patients with relapsed and refractory T-cell lymphoma. At that time, the study was expected to complete in December 2016

PATENTS……..WO 11/055215 ,  WO 12/151525.

• Antineoplastics; Small molecules
• Mechanism of Action Phosphatidylinositol 3 kinase delta inhibitors; Phosphatidylinositol 3 kinase gamma inhibitors

• Phase I Haematological malignancies
• Preclinical Multiple myeloma

 

Swaroop K. V. S. Vakkalanka,
COMPANY	Rhizen Pharmaceuticals Sa

https://clinicaltrials.gov/ct2/show/NCT02017613

 

PI3K delta/gamma inhibitor RP6530 An orally active, highly selective, small molecule inhibitor of the delta and gamma isoforms of phosphoinositide-3 kinase (PI3K) with potential immunomodulating and antineoplastic activities. Upon administration, PI3K delta/gamma inhibitor RP6530 inhibits the PI3K delta and gamma isoforms and prevents the activation of the PI3K/AKT-mediated signaling pathway. This may lead to a reduction in cellular proliferation in PI3K delta/gamma-expressing tumor cells. In addition, this agent modulates inflammatory responses through various mechanisms, including the inhibition of both the release of reactive oxygen species (ROS) from neutrophils and tumor necrosis factor (TNF)-alpha activity. Unlike other isoforms of PI3K, the delta and gamma isoforms are overexpressed primarily in hematologic malignancies and in inflammatory and autoimmune diseases. By selectively targeting these isoforms, PI3K signaling in normal, non-neoplastic cells is minimally impacted or not affected at all, which minimizes the side effect profile for this agent. Check for active clinical trials using this agent. (NCI Thesaurus)

Company	Rhizen Pharmaceuticals S.A.
Description	Dual phosphoinositide 3-kinase (PI3K) delta and gamma inhibitor
Molecular Target	Phosphoinositide 3-kinase (PI3K) delta ; Phosphoinositide 3-kinase (PI3K) gamma
Mechanism of Action	Phosphoinositide 3-kinase (PI3K) delta inhibitor; Phosphoinositide 3-kinase (PI3K) gamma inhibitor
Therapeutic Modality	Small molecule

 

Dual PI3Kδ/γ Inhibition By RP6530 Induces Apoptosis and Cytotoxicity In B-Lymphoma Cells

 Swaroop Vakkalanka, PhD*,¹, Srikant Viswanadha, Ph.D.*,², Eugenio Gaudio, PhD*,³, Emanuele Zucca, MD⁴, Francesco Bertoni, MD⁵, Elena Bernasconi, B.Sc.*,³, Davide Rossi, MD, Ph.D.*,⁶, and Anastasios Stathis, MD*,⁷

 ¹Rhizen Pharmaceuticals S A, La Chaux-de-Fonds, Switzerland, ²Incozen Therapeutics Pvt. Ltd., Hyderabad, India, ³Lymphoma & Genomics Research Program, IOR-Institute of Oncology Research, Bellinzona, Switzerland, ⁴IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland, ⁵Lymphoma Unit, IOSI-Oncology Institute of Southern Switzerland, Bellinzona, Switzerland, ⁶Italian Multiple Myeloma Network, GIMEMA, Italy, ⁷Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

November 15, 2013; Blood: 122 (21)

RP6530 is a potent and selective dual PI3Kδ/γ inhibitor that inhibited growth of B-cell lymphoma cell lines with a concomitant reduction in the downstream biomarker, pAKT. Additionally, the compound showed cytotoxicity in a panel of lymphoma primary cells. Findings provide a rationale for future clinical trials in B-cell malignancies.

POSTER SESSIONS

Dual PI3Kδ/γ Inhibition By RP6530 Induces Apoptosis and Cytotoxicity In B-Lymphoma Cells

Blood 2013 122:4411; published ahead of print December 6, 2013

Swaroop Vakkalanka, Srikant Viswanadha, Eugenio Gaudio, Emanuele Zucca, Francesco Bertoni, Elena Bernasconi, Davide Rossi, Anastasios Stathis

• Dual PI3K delta/gamma Inhibition By RP6530 Induces Apoptosis and Cytotoxicity
• RP6530, a novel, small molecule PI3K delta/gamma
• Activity and selectivity of RP6530 for PI3K delta and gamma isoforms

Introduction Activation of the PI3K pathway triggers multiple events including cell growth, cell cycle entry, cell survival and motility. While α and β isoforms are ubiquitous in their distribution, expression of δ and γ is restricted to cells of the hematopoietic system. Because these isoforms contribute to the development, maintenance, transformation, and proliferation of immune cells, dual targeting of PI3Kδ and γ represents a promising approach in the treatment of lymphomas. The objective of the experiments was to explore the therapeutic potential of RP6530, a novel, small molecule PI3Kδ/γ inhibitor, in B-cell lymphomas.

Methods Activity and selectivity of RP6530 for PI3Kδ and γ isoforms and subsequent downstream activity was determined in enzyme and cell-based assays. Additionally, RP6530 was tested for potency in viability, apoptosis, and Akt phosphorylation assays using a range of immortalized B-cell lymphoma cell lines (Raji, TOLEDO, KG-1, JEKO, OCI-LY-1, OCI-LY-10, MAVER, and REC-1). Viability was assessed using the colorimetric MTT reagent after incubation of cells for 72 h. Inhibition of pAKT was estimated by Western Blotting and bands were quantified using ImageJ after normalization with Actin. Primary cells from lymphoid tumors [1 chronic lymphocytic leukemia (CLL), 2 diffuse large B-cell lymphomas (DLBCL), 2 mantle cell lymphoma (MCL), 1 splenic marginal zone lymphoma (SMZL), and 1 extranodal MZL (EMZL)] were isolated, incubated with 4 µM RP6530, and analyzed for apoptosis or cytotoxicity by Annexin V/PI staining.

Results RP6530 demonstrated high potency against PI3Kδ (IC₅₀=24.5 nM) and γ (IC₅₀=33.2 nM) enzymes with selectivity over α (>300-fold) and β (>100-fold) isoforms. Cellular potency was confirmed in target-specific assays, namely anti-FcεR1-(EC₅₀=37.8 nM) or fMLP (EC₅₀=39.0 nM) induced CD63 expression in human whole blood basophils, LPS induced CD19+ cell proliferation in human whole blood (EC₅₀=250 nM), and LPS induced CD45R+ cell proliferation in mouse whole blood (EC₅₀=101 nM). RP6530 caused a dose-dependent inhibition (>50% @ 2-7 μM) in growth of immortalized (Raji, TOLEDO, KG-1, JEKO, REC-1) B-cell lymphoma cells. Effect was more pronounced in the DLBCL cell lines, OCI-LY-1 and OCI-LY-10 (>50% inhibition @ 0.1-0.7 μM), and the reduction in viability was accompanied by corresponding inhibition of pAKT with EC₅₀ of 6 & 70 nM respectively. Treatment of patient-derived primary cells with 4 µM RP6530 caused an increase in cell death. Fold-increase in cytotoxicity as evident from PI+ staining was 1.6 for CLL, 1.1 for DLBCL, 1.2 for MCL, 2.2 for SMZL, and 2.3 for EMZL. Cells in early apotosis (Annexin V+/PI-) were not different between the DMSO blank and RP6530 samples.

Conclusions RP6530 is a potent and selective dual PI3Kδ/γ inhibitor that inhibited growth of B-cell lymphoma cell lines with a concomitant reduction in the downstream biomarker, pAKT. Additionally, the compound showed cytotoxicity in a panel of lymphoma primary cells. Findings provide a rationale for future clinical trials in B-cell malignancies.

Disclosures:Vakkalanka:Rhizen Pharmaceuticals, S.A.: Employment, Equity Ownership; Incozen Therapeutics Pvt. Ltd.: Employment, Equity Ownership.Viswanadha:Incozen Therapeutics Pvt. Ltd.: Employment. Bertoni:Rhizen Pharmaceuticals SA: Research Funding.

 

PI3K Dual Inhibitor (RP-6530)

---

Therapeutic Area	Respiratory , Oncology – Liquid Tumors , Rheumatology	Molecule Type	Small Molecule
Indication	Peripheral T-cell lymphoma (PTCL) , Non-Hodgkins Lymphoma , Asthma , Chronic Obstructive Pulmonary Disease (COPD) , Rheumatoid Arthritis
Development Phase	Phase I	Rt. of Administration	Oral

Description

Rhizen is developing dual PI3K gamma/delta inhibitors for liquid tumors and inflammatory conditions.

Situation Overview

Dual Pl3K inhibition is strongly implicated as an intervention treatment in allergic and non-allergic inflammation of the airways and autoimmune diseases manifested by a reduction in neutrophilia and TNF in response to LPS. Scientific evidence for PI3-kinase involvement in various cellular processes underlying asthma and COPD stems from inhibitor studies and gene-targeting approaches, which makes it a potential target for treatment of respiratory disease. Resistance to conventional therapies such as corticosteroids in several patients has been attributed to an up-regulation of the PI3K pathway; thus, disruption of PI3K signaling provides a novel strategy aimed at counteracting the immuno-inflammatory response. Given the established criticality of these isoforms in immune surveillance, inhibitors specifically targeting the ? and ? isoforms would be expected to attenuate the progression of immune response encountered in most variations of airway inflammation and arthritis.

Mechanism of Action

While alpha and beta isoforms are ubiquitous in their distribution, expression of delta and gamma is restricted to circulating hematogenous cells and endothelial cells. Unlike PI3K-alpha or beta, mice lacking expression of gamma or delta do not show any adverse phenotype indicating that targeting of these specific isoforms would not result in overt toxicity. Dual delta/gamma inhibition is strongly implicated as an intervention strategy in allergic and non-allergic inflammation of the airways and other autoimmune diseases. Scientific evidence for PI3K-delta and gamma involvement in various cellular processes underlying asthma and COPD stems from inhibitor studies and gene-targeting approaches. Also, resistance to conventional therapies such as corticosteroids in several COPD patients has been attributed to an up-regulation of the PI3K delta/gamma pathway. Disruption of PI3K-delta/gamma signalling therefore provides a novel strategy aimed at counteracting the immuno-inflammatory response. Due to the pivotal role played by PI3K-delta and gamma in mediating inflammatory cell functionality such as leukocyte migration and activation, and mast cell degranulation, blocking these isoforms may also be an effective strategy for the treatment of rheumatoid arthritis as well.

Given the established criticality of these isoforms in immune surveillance, inhibitors specifically targeting the delta and gamma isoforms would be expected to attenuate the progression of immune response encountered in airway inflammation and rheumatoid arthritis.

 

http://www.rhizen.com/images/backgrounds/pi3k%20delta%20gamma%20ii.pngtps:/

Clinical Trials

Rhizen has identified an orally active Lead Molecule, RP-6530, that has an excellent pre-clinical profile. RP-6530 is currently in non-GLP Tox studies and is expected to enter Clinical Development in H2 2013.

In December 2013, Rhizen announced the start of a Phase I clinical trial. The study entitled A Phase-I, Dose Escalation Study to Evaluate Safety and Efficacy of RP6530, a dual PI3K delta /gamma inhibitor, in patients with Relapsed or Refractory Hematologic Malignancies is designed primarily to establish the safety and tolerability of RP6530. Secondary objectives include clinical efficacy assessment and biomarker response to allow dose determination and potential patient stratification in subsequent expansion studies.

 

Partners by Region

Rhizen’s pipeline consists of internally discovered (with 100% IP ownership) novel small molecule programs aimed at high value markets of Oncology, Immuno-inflammtion and Metabolic Disorders. Rhizen has been successful in securing critical IP space in these areas and efforts are on for further expansion in to several indications. Rhizen seeks partnerships to unlock the potential of these valuable assets for further development from global pharmaceutical partners. At present global rights on all programs are available and Rhizen is flexible to consider suitable business models for licensing/collaboration.

In 2012, Rhizen announced a joint venture collaboration with TG Therapeutics for global development and commercialization of Rhizen’s Novel Selective PI3K Kinase Inhibitors. The selected lead RP5264 (hereafter, to be developed as TGR-1202) is an orally available, small molecule, PI3K specific inhibitor currently being positioned for the treatment of hematological malignancies.

PATENT

WO2014195888, DUAL SELECTIVE PI3 DELTA AND GAMMA KINASE INHIBITORS

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014195888

….Intermediates

PATENT

WO 2011055215

http://www.google.com.ar/patents/WO2011055215A2?cl=en

PATENT

WO 2012151525

https://www.google.com/patents/WO2012151525A9?cl=en

This scheme provides a synthetic route for the preparation of compound of formula wherein all the variables are as described herein in above

15 14 10 12 12a

REFERENCES

April 2015, preclinical data were presented at the 106th AACR Meeting in Philadelphia, PA. RP-6530 had GI50 values of 17,028 and 22,014 nM, respectively

December 2014, data were presented at the 56th ASH Meeting in San Francisco, CA.

December 2013, preclinical data were presented at the 55th ASH Meeting in New Orleans, LA.

June 2013, preclinical data were presented at the 18th Annual EHA Congress in Stockholm, Sweden. RP-6530 inhibited PI3K delta and gamma isoforms with IC50 values of 24.5 and 33.2 nM, respectively.

• 01 Sep 2015 Phase-I clinical trials in Hematological malignancies (Second-line therapy or greater) in USA (PO) (NCT02567656)
• 18 Nov 2014 Preclinical trials in Multiple myeloma in Switzerland (PO) prior to November 2014
• 18 Nov 2014 Early research in Multiple myeloma in Switzerland (PO) prior to November 2014

 

WO2011055215A2	Nov 3, 2010	May 12, 2011	Incozen Therapeutics Pvt. Ltd.	Novel kinase modulators
WO2012151525A1	May 4, 2012	Nov 8, 2012	Rhizen Pharmaceuticals Sa	Novel compounds as modulators of protein kinases
WO2013164801A1	May 3, 2013	Nov 7, 2013	Rhizen Pharmaceuticals Sa	Process for preparation of optically pure and optionally substituted 2- (1 -hydroxy- alkyl) – chromen – 4 – one derivatives and their use in preparing pharmaceuticals
US20110118257		May 19, 2011	Rhizen Pharmaceuticals Sa	Novel kinase modulators
US20120289496	May 4, 2012	Nov 15, 2012	Rhizen Pharmaceuticals Sa	Novel compounds as modulators of protein kinases

WO 2014195888

WO 2011055215

 

 

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Glucokinase target for type 2 diabetes

Posted in Chemical Biology and its relations to Metabolic Disease, Clinical & Translational, Curation, Diabetes Mellitus, FDA Regulatory Affairs, Gastroenterology, Lasers and photonics, Liver & Digestive Diseases Research, Metabolism, Patents, Pharmaceutical Drug Discovery, Pharmaceutical R&D Investment, tagged glucokinase activator, type 2 diabetes on November 27, 2015| Leave a Comment »

Glucokinase target for type 2 diabetes

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Pfizer’s PF 04991532 a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus
DR ANTHONY MELVIN CRASTO, WORLD DRUG TRACKER
http://newdrugapprovals.org/2015/11/27/pfizers-pf-04991532-a-hepatoselective-glucokinase-activator-clinical-candidate-for-treating-type-2-diabetes-mellitus/

 

PF 04991532

GKA PF-04991532

(S)-6-{3-cyclopentyl-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]propanamido}nicotinic acid

(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid

(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid

MW 396.36, MF C₁₈ H₁₉ F₃ N₄ O₃

CAS 1215197-37-7

3-​Pyridinecarboxylic acid, 6-​[[(2S)​-​3-​cyclopentyl-​1-​oxo-​2-​[4-​(trifluoromethyl)​-​1H-​imidazol-​1-​yl]​propyl]​amino]​-

http://www.biochemj.org/content/441/3/881

 

Type 2 diabetes mellitus (T2DM) is a rapidly expanding public epidemic affecting over 300 million people worldwide. This disease is characterized by elevated fasting plasma glucose (FPG), insulin resistance, abnormally elevated hepatic glucose production (HGP), and reduced glucose-stimulated insulin secretion (GSIS). Moreover, long-term lack of glycemic control increases risk of complications from neuropathic, microvascular, and macrovascular diseases.

The standard of care for T2DM is metformin followed by sulfonylureas, dipeptidyl peptidase-4 (DPP-IV) inhibitors, and thiazolidinediones (TZD) as second line oral therapies. As disease progression continues, patients typically require injectable agents such as glucagon-like peptide-1 (GLP-1) analogues and, ultimately, insulin to help maintain glycemic control. Despite these current therapies, many patients still remain unable to safely achieve and maintain tight glycemic control, placing them at risk of diabetic complications and highlighting the need for novel therapeutic options.

 

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia.

While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index.

 

Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood glucose levels. Two major forms of diabetes are recognized. Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin. Type II diabetes, or non-insulin dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues and cells to respond appropriately to insulin. Aggressive control of NIDDM with medication is essential; otherwise it can progress into IDDM.

As blood glucose increases, it is transported into pancreatic beta cells via a glucose transporter. Intracellular mammalian glucokinase (GK) senses the rise in glucose and activates cellular glycolysis, i.e. the conversion of glucose to glucose-6-phosphate, and subsequent insulin release. Glucokinase is found principally in pancreatic β-cells and liver parenchymal cells. Because transfer of glucose from the blood into muscle and fatty tissue is insulin dependent, diabetics lack the ability to utilize glucose adequately which leads to undesired accumulation of blood glucose (hyperglycemia). Chronic hyperglycemia leads to decreases in insulin secretion and contributes to increased insulin resistance. Glucokinase also acts as a sensor in hepatic parenchymal cells which induces glycogen synthesis, thus preventing the release of glucose into the blood. The GK processes are thus critical for the maintenance of whole body glucose homeostasis.

It is expected that an agent that activates cellular GK will facilitate glucose-dependent secretion from pancreatic beta cells, correct postprandial hyperglycemia, increase hepatic glucose utilization and potentially inhibit hepatic glucose release. Consequently, a GK activator may provide therapeutic treatment for NIDDM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity.

Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM (Moller, D. E., “New drug targets for Type II diabetes and the metabolic syndrome” Nature414; 821-827, (2001)): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents.

Ideally, an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are independent from the actions of insulin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.

Substituted heteroaryls, particularly pyridones, have been implicated in mediating GK and may play a significant role in the treatment of NIDDM. For example, U.S. Patent publication No. 2006/0058353 and PCT publication Nos. WO2007/043638, WO2007/043638, and WO2007/117995 recite certain heterocyclic derivatives with utility for the treatment of diabetes. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabetes, particularly NIDDM.

 

 

 

PATENT

US 20100063063

http://www.google.com/patents/US20100063063

SYNTHESIS CONSTRUCTION

6-aminonicotinic acid

 

BENZYL BROMIDE

 

FIRST KEY INTERMEDIATE

 

SECOND SERIES FOR NEXT INTERMEDIATE

CONDENSED WITH

4-Trifluoromethyl-1H-imidazole

TO  GIVE PRODUCT SHOWN BELOW

 

(S)-methyl 3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate (I-8a)

 

CONVERTED TO ACID CHLORIDE, (S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoyl chloride (I-8c)

AND CONDENSED WITH

WILL GIVE BENZYL DERIVATIVE

THEN DEBENZYLATION TO FINAL PRODUCT

 

 

 

¹H NMR (400 MHz, DMSO-d₆) δ 13.10-13.25 (1H), 11.44 (1H), 8.83 (1H), 8.23-8.26 (1H), 8.09-8.12 (1H), 7.94-7.95 (2H), 5.22-5.26 (1H), 2.06-2.17 (2H), 1.29-1.64 (8H), 1.04-1.07 (1H); m/z 397.3 (M+H)⁺.

 

Organic Process Research & Development (2012), 16(10), 1635-1645

http://pubs.acs.org/doi/abs/10.1021/op300194c

This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-prone α-aryl carboxylate functionality. In particular, a T3P-mediated amidation process was optimized for the coupling of a racemization-prone acid substrate and a relatively non-nucleophilic amine. Furthermore, an unusually hydrolytically-labile amide in the API also complicated the synthesis and isolation of drug substance. The evolution of the process over multiple campaigns is presented, resulting in the preparation of over 110 kg of glucokinase activator.

(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid (1)

 

Journal of Medicinal Chemistry (2012), 55(3), 1318-1333

http://pubs.acs.org/doi/abs/10.1021/jm2014887

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure–activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

Bioorganic & Medicinal Chemistry Letters (2013), 23(24), 6588-6592

http://www.sciencedirect.com/science/article/pii/S0960894X13012638

 

Figure 1.

Structure of Hepatoselective GKA PF-04991532 (1).

 

Pfizer’s PF 04937319 glucokinase activators for the treatment of Type 2 diabetes
DR ANTHONY MELVIN CRASTO, WORLD DRUG TRACKER
http://newdrugapprovals.org/2015/11/27/pfizers-pf-04937319-glucokinase-activators-for-the-treatment-of-type-2-diabetes/

PF 04937319

N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide

MW 432.43

MF C₂₂ H₂₀ N₆ O₄

CAS 1245603-92-2

2-​Pyrimidinecarboxamid​e, N,​N-​dimethyl-​5-​[[2-​methyl-​6-​[[(5-​methyl-​2-​pyrazinyl)​amino]​carbonyl]​-​4-​benzofuranyl]​oxy]​-

N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide

Pfizer Inc. clinical candidate currently in Phase 2 development.

CLINICAL TRIALS

A trial to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of PF-04937319 in subjects with type 2 diabetes mellitus (NCT01044537)

Multiple dose study of PF-04937319 in patients with type 2 diabetes (NCT01272804)

Phase 2 study to evaluate safety and efficacy of investigational drug – PF04937319 in patients with type 2 diabetes (NCT01475461)

 

SYNTHESIS

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification ofN,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.

 

It is expected that an agent that activates cellular GK will facilitate glucose-dependent secretion from pancreatic beta cells, correct postprandial hyperglycemia, increase hepatic glucose utilization and potentially inhibit hepatic glucose release. Consequently, a GK activator may provide therapeutic treatment for NIDDM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity. Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM (Moller, D. E., “New drug targets for Type 2 diabetes and the metabolic syndrome” Nature 414; 821 -827, (2001 )): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents. Ideally, an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are independent from the actions of insulin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.

Substituted heteroaryls, particularly pyridones, have been implicated in mediating GK and may play a significant role in the treatment of NIDDM. For example, U.S. Patent publication No. 2006/0058353 and PCT publication No’s. WO2007/043638, WO2007/043638, and WO2007/117995 recite certain heterocyclic derivatives with utility for the treatment of diabetes. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabetes, particularly NIDDM.

 

Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

Jeffrey A. Pfefferkorn,*^a   et al

*Corresponding authors

^aPfizer Worldwide Research & Development, Eastern Point Road, Groton
E-mail: jeffrey.a.pfefferkorn@pfizer.com
Tel: +860 686 3421

Med. Chem. Commun., 2011,2, 828-839

DOI: 10.1039/C1MD00116G

http://pubs.rsc.org/en/content/articlelanding/2011/md/c1md00116g/unauth#!divAbstract

http://www.rsc.org/suppdata/md/c1/c1md00116g/c1md00116g.pdf

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification ofN,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.

N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide (28).

 

PAPER

 

http://pubs.rsc.org/en/content/articlelanding/2013/md/c2md20317k#!divAbstract

 

PAPER

Bioorganic & Medicinal Chemistry Letters (2013), 23(16), 4571-4578

http://www.sciencedirect.com/science/article/pii/S0960894X13007452

Figure 1.

Glucokinase activators 1 and 2.

 

PATENT

Pfizer Inc.

WO 2010103437

https://www.google.co.in/patents/WO2010103437A1?cl=en

Scheme I outlines the general procedures one could use to provide compounds of the present invention having Formula (I).

Preparations of Starting Materials and Key Intermediates

 

 

Beebe, D.A.; Ross, T.T.; Rolph, T.P.; Pfefferkorn, J.A.; Esler, W.P.
The glucokinase activator PF-04937319 improves glycemic control in combination with exercise without causing hypoglycemia in diabetic rats
74th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 13-17, San Francisco) 2014, Abst 1113-P

 

Amin, N.B.; Aggarwal, N.; Pall, D.; Paragh, G.; Denney, W.S.; Le, V.; Riggs, M.; Calle, R.A.
Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes
Diabetes Obes Metab 2015, 17(8): 751

 

Study to compare single dose of three modified release formulations of PF-04937319 with immediate release material-sparing-tablet (IR MST) formulation previously studied in adults with type 2 diabetes mellitus (NCT02206607)

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blocking copper transport in cancer cells

Posted in Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Biology and its relations to Metabolic Disease, Clinical & Translational, Curation, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA, Gastroenterology, Gene Regulation, Innovations, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, International Global Work in Pharmaceutical, Investment in Technological Breakthrough, Liver & Digestive Diseases Research, Metabolism, Metabolomics, Patents, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, tagged anticancer agent, binding to chaperone, copper transport, liver on November 11, 2015| Leave a Comment »

blocking copper transport in cancer cells

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

DC_AC50, selective way of blocking copper transport in cancer cells

http://newdrugapprovals.org/2015/11/11/dc_ac50-selective-way-of-blocking-copper-transport-in-cancer-cells/

Dr. Melvin Crasto, World Drug Tracker

Jing Chen of Emory University School of Medicine, Hualiang Jiang of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, Chuan He of the University of Chicago, and coworkers have now developed a selective way of blocking copper transport in cancer cells (Nat. Chem. 2015, DOI: 10.1038/nchem.2381). By screening a database of 200,000 druglike small molecules, the researchers discovered a promising compound, DC_AC50, for cancer treatment. They zeroed in on the compound by testing how well database hits inhibited a protein-protein interaction leading to copper transport and reduced proliferation of cancer cells.

 

DC_AC50

3-amino-N-(2-bromo-4,6-difluorophenyl)-6,7-dihydro-5H- cyclopenta [b] thieno [3,2-e] pyridine-2-carboxamide

licensed DC_AC50 to Suring Therapeutics, in Suzhou, China

INNOVATORS  Jing Chen of Emory University School of Medicine, Hualiang Jiang of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, Chuan He of the University of Chicago, and coworkers

 

http://www.nature.com/nchem/journal/vaop/ncurrent/images/nchem.2381-f1.jpg

 

COPPER TRANSPORT

Chaperone proteins (green) transfer copper ions to copper-dependent proteins (lilac) via ligand exchange between two cysteines (-SH groups) on each protein. DC_AC50 binds the chaperone and inhibits this interaction.

Credit: Nat. Chem.

Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

Jing Wang, Cheng Luo, Changliang Shan, Qiancheng You, Junyan Lu, Shannon Elf, Yu Zhou, Yi Wen, Jan L. Vinkenborg, Jun Fan, et al.

Nature Chemistry, (2015)   http://dx.doi.org:/10.1038/nchem.2381

Jing Chen of Emory University School of Medicine, Hualiang Jiang of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences,Chuan He of the University of Chicago, and coworkers have now developed a selective way of blocking copper transport in cancer cells (Nat. Chem. 2015, DOI: 10.1038/nchem.2381). By screening a database of 200,000 druglike small molecules, the researchers discovered a promising compound, DC_AC50, for cancer treatment. They zeroed in on the compound by testing how well database hits inhibited a protein-protein interaction leading to copper transport and reduced proliferation of cancer cells.

http://cen.acs.org/content/cen/articles/93/web/2015/11/Agent-Fight-Cancer-Inhibiting-Copper/_jcr_content/articlebody/subpar/articlemedia_0.img.jpg/1447092911801.jpg

 

Scientists had already found a molecule, tetrathiomolybdate, that interferes with copper trafficking and have tested it in clinical trials against cancer. But tetrathiomolybdate is a copper chelator: It inhibits copper transport in cells by nonselectively sequestering copper ions. Sometimes, the chelator snags too much copper, inhibiting essential copper-based processes in normal cells and causing side effects.

In contrast, DC_AC50 works by inhibiting interactions between proteins in the copper-trafficking pathway: It prevents chaperone proteins, called Atox1 and CCS, from passing copper ions to enzymes that use them to run vital cellular processes. Cancer cells are heavy users of Atox1 and CCS, so DC_AC50 affects cancer cells selectively.

The team has licensed DC_AC50 to Suring Therapeutics, in Suzhou, China, for developing anticancer therapies. The group also plans to further tweak DC_AC50 to develop more-potent versions.

Thomas O’Halloran of Northwestern University, who has studied tetrathiomolybdate, comments that “the challenge in drug design is hitting one of these copper-dependent processes without messing with housekeeping functions that normal cells depend upon. DC_AC50 appears to block the function of copper metallochaperone proteins without interacting directly with their cargo, copper ions. As the first member of a new class of inhibitors, it provides a new way to interrogate the physiology of copper trafficking disorders and possibly intervene.”

PATENT

http://www.google.com/patents/WO2014116859A1?cl=en

 

COMPD IS LC-1 COMPD 50

 

NMR and mass spectral data: LC-1 (Compound 50)- 3-amino-N-(2-bromo-4,6-difluorophenyl)-6,7-dihydro-5H- cyclopenta [b] thieno [3,2-e] pyridine-2-carboxamide

1H NMR (CDCI3, 400 MHz) δ 9.15 (s, 1H), 7.61 (s, 1H), 7.13(m, 1H), 6.60 (m, 1H), 6.27 (s, 2H), 3.20 (t, 2H), 2.98 (t, 2H), 2.39 (m, 2H); ESI-MS (EI) m/z 422 (M⁺)

 

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Phase I/II Hepato-specific Glucokinase Activator

Posted in Cell Biology, Chemical Biology and its relations to Metabolic Disease, Clinical & Translational, Curation, Diabetes Mellitus, Diagnostics and Lab Tests, Disease Biology, Endocrine Diseases, Enzymes and isoenzymes, Epigenetics and Cardiovascular Risks, FDA, Gastroenterology, Gene Regulation, Genomic Testing: Methodology for Diagnosis, Innovations, Intellectual Property, International Global Work in Pharmaceutical, Kinase, Metabolism, Metabolomics, Nutrition, Origins of Cardiovascular Disease, Patents, Personal Health Applications: Tech Innovations serves HealhCare, Pharmaceutical Analytics, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, tagged glucokinase activator, glucokinase inhibitor, liver specificity, pharmaceutical innovation, T2DM on November 10, 2015| Leave a Comment »

Phase I/II Hepato-specific Glucokinase Activator

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Advinus Therapeutics announced that it has successfully completed a 14-day POC study in 60 Type II diabetic patients on its lead molecule, GKM-001, a glucokinase activator. The results of the trial show effective glucose lowering across all doses tested without any incidence of hypoglycemia or any other clinically relevant adverse events.

GKM-001 is differentiated from most other GK molecules that are in development, or have been discontinued, due to its novel liver selective mechanism of action.

GKM-001 belongs to a novel class of molecules for treatment of type II diabetes. It is an activator of Glucokinase (GK), a glucose-sensing enzyme found mainly in the liver and pancreas. Being liver selective, GKM-001 mostly activates GK in the liver and not in pancreas, which is its key differentiation from most competitor molecules that activate GK in pancreas as well.

GKM 001 in pipeline for Diabetes by Advinus by DR ANTHONY MELVIN CRASTO Ph.D

https://newdrugapprovals.files.wordpress.com/2015/11/ad-1.jpg

GKM 001

Advinus Therapeutics Private L,

A glucokinase activator for treatment of type II diabetes, currently in PI. Advinus is actively exploring partnership options to expedite further development and WW marketing of GKM-001.

Company	Advinus Therapeutics Ltd.
Description	Activator of glucokinase (GCK; GK)
Molecular Target	Glucokinase (GCK) (GK)
Mechanism of Action	Glucokinase activator
Therapeutic Modality	Small molecule

Latest Stage of Development	Phase I/II
Standard Indication	Diabetes
Indication Details	Treat Type II diabetes

PATENT

https://www.google.co.in/patents/WO2009047798A2?cl=en

Example Cl : (-)-{5-ChIoro-2-[2-(4-cyclopropanesulfonylphenyI)-2-(2,4- difluorophenoxy)acetylamino]thiazol-4-yl}-acetic acid, ethyl ester
¹H NMR(400 MHz, CDCl₃): δ 1.06-1.08 (m, 2H), 1.30 (t, J=7.2 Hz, 3H), 1.33-1.38 (m, 2H), 2.42-2.50 (m, IH), 3.73 (d, J=2 Hz, 2H), 4.22 (q, J=7.2 Hz ,2H), 5.75 (s, IH), 6.76- 6.77 (m, IH), 6.83-6.86 (m, IH), 6.90-6.98 (m, IH), 7.73 (d, J=8.4 Hz, 2H), 7.96 (d, J=8.4 Hz, 2H), 9.96 (bs, IH). MS (EI) m/z: 571.1 and 573.1 (M+ 1; for ³⁵Cl and ³⁷Cl respectively).

Examples C2 and C3 were prepared in analogues manner of example (Cl) from the appropriate chiral intermediate:

Example Dl : (+)-{5-Chloro-2-[2-(4-cyclopropanesulfonylphenyl)-2-(2,4- difluorophenoxy)acetylamino]thiazol-4-yl}acetic acid, ethyl ester

Advinus’ GK-activator Achieves Early POC for Diabetes

November 29 2011

Partnership Dialog Actively Underway

Advinus Therapeutics, a research-based pharmaceutical company founded by globally experienced industry executives and promoted by the TATA Group, announced that it has successfully completed a 14-day POC study in 60 Type II diabetic patients on its lead molecule, GKM-001, a glucokinase activator. The results of the trial show effective glucose lowering across all doses tested without any incidence of hypoglycemia or any other clinically relevant adverse events.

The clinical trials on GKM-001 validate the company’s pre-clinical hypothesis that a liver selective Glucokinase activator would not cause hypoglycemia (very low blood sugar), while showing robust efficacy.

“GKM-001 is differentiated from most other GK molecules that are in development, or have been discontinued, due to its novel liver selective mechanism of action. GKM-001 has a prolonged pharmacological effect and a half-life that should support a once a day dosing as both mono and combination therapy.” said Dr. Rashmi Barbhaiya, MD & CEO, Advinus Therapeutics. He added that Advinus is actively exploring partnership options to expedite further development and global marketing of GKM-001.

GKM-001 belongs to a novel class of molecules for treatment of type II diabetes. It is an activator of Glucokinase (GK), a glucose-sensing enzyme found mainly in the liver and pancreas. Being liver selective, GKM-001 mostly activates GK in the liver and not in pancreas, which is its key differentiation from most competitor molecules that activate GK in pancreas as well. The resulting increase in insulin secretion creates a potential for hypoglycemia-a risk GKM-001 is designed to avoid. Advinus has the composition of matter patent on GKM-001 for all major markets globally. Both the Single Ascending Dose data, in healthy and type II diabetics, and the Multiple Ascending Dose Study in Type II diabetics has shown that the molecule shows effective glucose lowering in a dose dependent manner and has excellent safety and tolerability profile over a 40-fold dose range. The pharmacokinetic properties of the molecule support once a day dosing. GKM-001 has the potential to be “First-in-Class” drug to address this large, growing and yet poorly addressed market.

Advinus also has identified a clinical candidate as a back-up to GKM-001, which is structurally different. In its portfolio, the company has a growing pipeline for COPD, sickle cell disease, inflammatory bowel disease, type 2 diabetes, acute and chronic pain and rheumatoid arthritis in various stages of late discovery and pre-clinical development.

Advinus Therapeutics team discovers novel molecule for treatment of diabetes

• The first glucokinase modulator discovered and developed in India 
• A new concept for the management of diabetes for patients, globally 
• 100 per cent ‘made in India’ molecule for the treatment of diabetes 
• IND approved by DGCI, Phase I clinical trial shows excellent safety and tolerance profiles with efficacy

Bangalore: Advinus Therapeutics (Advinus), the research-based pharmaceutical company founded by leading global pharmaceutical executives and promoted by the Tata group, today, announced the discovery of a novel molecule for the treatment of type II diabetes — GKM-001.The molecule is an activator of glucokinase; an enzyme that regulates glucose balance and insulin secretion in the body.

GKM-001 is a completely indigenously developed molecule and the initial clinical trials have shown excellent results for both safety and efficacy.

“Considering past failures of other companies on this target, our discovery programme primarily focused on identifying a molecule that would be efficacious without causing hypoglycaemia; a side effect associated with most compounds developed for this target.

“Recently completed Phase I data indicate that Advinus’ GKM–001 is a liver selective molecule that has overcome the biggest clinical challenge of hypoglycaemia. GKM-001 is differentiated from most other GK molecules in development due to this novel mechanism of action,” said Dr Rashmi Barbhaiya, MD and CEO, Advinus Therapeutics.

He further added, “We are very proud that GKM-001 is 100 per cent Indian. Advinus’s discovery team in Pune discovered the molecule and entire preclinical development was carried out at our centre in Bangalore. The Investigational New Drug (IND) application was filed with the DGCI for approval to initiate clinical trials in India within 34 months of initiation of the discovery programme. Subsequent to the approval of the IND, we have completed the Phase I Single Ascending Dose study in India within two months.”

GKM-001 is a novel molecule for the treatment of type II diabetes. It is the first glucokinase modulator discovered and developed in India and has potential to be both first or best in class. The success in discovering GKM-001 is attributed to the science-driven efforts in Advinus laboratories and ‘breaking the conventional mold’ for selection of a drug candidate. Advinus has ‘composition of matter’ patent on the molecule for all major markets globally. Glucokinase as a class of target is considered to be novel as currently there is no product in the market or in late clinical trials. The strategy for early clinical development revolved around assessing safety (particularly hypoglycaemia) and early assessment of therapeutic activity (glucose lowering and other biomarkers) in type II diabetics. The Phase I data, in both healthy and type II diabetics, shows excellent safety and tolerability over a 40-fold dose range and desirable pharmacokinetic properties consistent with ‘once a day’ dosing. The next wave of clinical studies planned continues on this strategy of early testing in type II diabetics.

Right behind the lead candidate GKM-001, Advinus has a rich pipeline of back up compounds on the same target. These include several structurally different compounds with diverse potency, unique pharmacology and tissue selectivity. Having discovered the molecule with early indication of wide safety margins, desired efficacy and pharmacokinetic profiles, the company now seeks to out-licence GKM-001 and its discovery portfolio.

Liver Selective Glucokinase Activation for Treating Type 2 Diabetes: Translation fromMouse to Man

Kasim A. Mookhtiar, , Debnath Bhuniya, Siddhartha De, Anita Chugh, Jayasagar

Gundu, Venkata Palle, Dhananjay Umrani, Nimish Vachharajani, Vikram

Ramanathan and Rashmi H. Barbhaiya

Advinus Therapeutics Ltd, Hinjewadi, Pune – 411057, and Peenya Industrial Area,

Bangalore – 560058, India

REFERENCES

http://www.asiabiotech.com/publication/apbn/14/english/preserved-docs/1410/0043_0043.pdf

http://www.thepharmatimes.in/index.php/news/general/national/268-advinus-gk-activator-achieves-early-poc-for-diabetes

 http://ctri.nic.in/clinicaltrials/pmaindet2.php?trialid=2869

patent

wo 2008104994

wo 2008 149382

wo 2009047798

WO2008104994A2*

25 Feb 2008

4 Sep 2008

Advinus Therapeutics Private L

2,2,2-tri-substituted acetamide derivatives as glucokinase activators, their process and pharmaceutical application

///////GKM 001, pipeline, Diabetes, Advinus, type II diabetes, glucokinase modulator, Rashmi Barbhaiya

DR ANTHONY MELVIN CRASTO Ph.D | November 10, 2015 at 12:55 pm | Tags: Advinus,DIABETES, GKM 001, glucokinase modulator, pipeline, Rashmi Barbhaiya, type II diabetes | Categories: Uncategorized | URL: http://wp.me/p38LX5-44G

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pathway and network analysis of complex ‘omics data

Posted in Clinical Diagnostics, Clinical Genomics, Commercialization, Computational Biology/Systems and Bioinformatics, Curation, Genetics & Pharmaceutical, Genome Biology, Health Economics and Outcomes Research, Health Law & Patient Safety, Innovations, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, Law and Medicine Conflicts, Metabolomics, Molecular Genetics & Pharmaceutical, Patents, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, RNA Biology, Cancer and Therapeutics, tagged discrepancy between the FDA and the manufacturer, Identify causal variants from human sequencing data, pathway and network analysis, Pathway Genomics on October 23, 2015| Leave a Comment »

pathway and network analysis of complex ‘omics data

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

While blood tests can be used to detect some cancers, the FDA said a San Diego company has no proof its blood test works in patients who have not already been diagnosed with some form of the disease.

WASHINGTON, Sept. 25 (UPI) — A San Diego company selling an early cancer detection test was notified by the U.S. Food and Drug Administration it can find no evidence the test actually works, and is concerned it could prove to be harmful for some people.

Pathway Genomics debuted its CancerIntercept test in early September with claims it can detect cancer cell DNA in the blood, picking up mutations linked to as many as 10 different cancers. The goal is to catch cancer early in people who are “otherwise healthy” and not showing symptoms of the disease.

“Based on our review of your promotional materials and the research publication cited above, we believe you are offering a high risk test that has not received adequate clinical validation and may harm the public health,” said FDA Deputy Director James L. Woods in a letter to the company.

CancerIntercept is billed by the company as a blood test looking for DNA fragments in the bloodstream and testing them for 96 genomic markers it says are found in several specific tumor types.

The direct-to-consumer test can be purchased through the Pathway Genomics website, with programs ranging from a one-time test to a quarterly “subscription” for people who want regular testing.

The company states, in several sections of its website, “the presence of one or more of these genomic markers in a patient’s bloodstream may indicate that the patient has a previously undetected cancer. However, the test is not diagnostic, and thus, follow-up screening and clinical testing would be required to confirm the presence or absence of a specific cancer in the patient.”

The FDA is concerned that people may seek treatment for tumors that do not require medical attention, or spend money and possibly seek out treatment they do not need at all — in either case, unnecessary treatment for cancer is potentially harmful to people, the agency said.

CancerIntercept has not been approved by the FDA for use as a medical device, nor has it been subjected to peer review as most tests of its type would be. The company published a white paper on its website which outlines how the test works, supporting its efficacy with references to several clinical trials on detection of mutated DNA in the bloodstream.

Glenn Braunstein, Chief Medical Officer at Pathway Genomics, told The VergePathway had validated its tests with “hundreds” of patients, though those patients had well-defined, often advanced cancers.

In the letter from the FDA, Woods requests the company provide a timeline for meeting with the agency to review plans for future longitudinal studies on the product and specific details on studies that have been conducted before it was made available to consumers.

http://www.upi.com/Health_News/2015/09/25/FDA-Start-ups-cancer-blood-test-may-be-harmful/4191443181676/

The clinical laboratory is an essential player in the treatment of cancer providing a diagnostic, potentially a prognostic, and follow-up treatment armamentarium.  The laboratory diagnostics industry has grown over the last half century into  a highly accurate, well regulated industry with highly automated and point of care technologies.  Prior to introduction, the tests that are put on the market have to be validated prior to introduction.

How are they validated?

The most common approach is for the test to be used concomitantly with treatment in a clinical trial. Measurements may be made prior to surgical biopsy and treatment, and at a month or 6 months to a year later.  The pharmaceutical and diagnostics industries are independent, even though a large company may have both pharmaceutical and diagnostic divisions.  Consequently, the integration of diagnostics and therapeutics occurs on the front lines of patient care.

How this discrepancy between the FDA and the manufacturer could occur is not clear because prior to introduction, the test would have to be rigorously reviewed by the American Association for Clinical Chemistry, the largest and most competent organization to cover the scientific work, having industry-based committees.  The only problem is that the companies may have products that are patented and have competing claims or interests. This is perhaps most likely to be problematic in the competitive environment of  genomics testing.

The company here reported on is Pathway Genomics, that offers Ingenuity for pathway and variant analysis.  There is no concern about the analysis methods, that are well studied.  The concern is the validation of such method for screening of patients without prior diagnosis.

Model, analyze, and understand the complex biological and chemical systems at the core of life science research with IPA

QIAGEN’S Ingenuity Pathway Analysis (IPA) has been broadly adopted by the life science research community and is cited in thousands of peer-reviewed journal articles.

https://youtu.be/_HDkjuxYRcY

https://youtu.be/_HDkjuxYRcY?t=25

For the analysis and interpretation of ’omics data

Market Leading Pathway Analysis

Unlock the insights buried in experimental data by quickly identifying relationships, mechanisms, functions, and pathways of relevance.

Predictive Causal Analytics

Powerful causal analytics at your fingertips help you to build a more complete regulatory picture and a better understanding of the biology underlying a given gene expression study.

NGS/RNA-Seq Data Analysis

Get a better understanding of the isoform-specific biology resulting from RNA-Seq experiments.

Identify causal variants from human sequencing data

http://www.ingenuity.com/wp-content/uploads/2014/01/variant-analyisis-interpretation.png

Rapidly Identify and Prioritize Variants

Ingenuity Variant Analysis combines analytical tools and integrated content to help you rapidly identify and prioritize variants by drilling down to a small, targeted subset of compelling variants based both upon published biological evidence and your own knowledge of disease biology. With Variant Analysis, you can interrogate your variants from multiple biological perspectives, explore different biological hypotheses, and identify the most promising variants for follow-up.

Variant Analysis used in NCI-60 Interpretation of Genomic Variants

The NCI-60 Data Set offers tremendous promise in the development and prescription of cancer drugs

97% of surveyed researchers are satisfied with the ease of use of Ingenuity Variant Analysis and we are honored that they chose to share the data through our Publish tool.

See the research verified by TechValidate

“Being a bioinformatician, I appreciated the speed and the complexity of analysis. Without Variant Analysis, I couldn’t have completed the analysis of 700 exomes in such a short time …. I found Variant Analysis very intuitive and easy to use.”

Francesco Lescai, Senior Research Associate in Genome Analysis, University College of London.

This appears to be the new rocky road to verification for validity in diagnostic and treatment application.

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Humanized Mice May Revolutionize Cancer Drug Discovery

Posted in BioTechnology - Venture Creation, BioTechnology - Venture Creation, Venture Capital, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Monoclonal Immunotherapy, Patents, Pharmaceutical Drug Discovery, Pharmacodynamics and Pharmacokinetics, tagged animal models of disease, Cancer - General, Cancer immunology, Cancer immunotherapy, Conditions and Diseases, Food and Drug Administration, health, humanized mice, immunomodulatory, Monoclonal antibodies, oncology, patient derived xenograft, preclinical testing, research, science on October 9, 2015| Leave a Comment »

Humanized Mice May Revolutionize Cancer Drug Discovery

Curator: Stephen J. Williams, Ph.D.

Word Cloud by Zach Day

Decades ago cancer research and the process of oncology drug discovery was revolutionized by the development of mice deficient in their immune system, allowing for the successful implantation of human-derived tumors. The ability to implant human tumors without rejection allowed researchers to study how the kinetics of human tumor growth in its three-dimensional environment, evaluate potential human oncogenes and drivers of oncogenesis, and evaluate potential chemotherapeutic therapies. Indeed, the standard preclinical test for antitumor activity has involved the subcutaneous xenograft model in immunocompromised (SCID or nude athymic) mice. More detail is given in the follow posts in which I describe some early pioneers in this work as well as the development of large animal SCID models:

Heroes in Medical Research: Developing Models for Cancer Research

The SCID Pig: How Pigs are becoming a Great Alternate Model for Cancer Research

The SCID Pig II: Researchers Develop Another SCID Pig, And Another Great Model For Cancer Research

This strategy (putting human tumor cells into immunocompromised mice and testing therapeutic genes and /or compounds) has worked extremely well for most cytotoxic chemotherapeutics (those chemotherapeutic drugs with mechanisms of action related to cell kill, vital cell functions, and cell cycle). For example the NCI 60 panel of human tumor cell lines has proved predictive for the chemosensitivity of a wide range of compounds.

• The NCI-60 panel has been used by the Developmental Therapeutics Program (DTP) of the U.S. National Cancer Institute (NCI) to screen >100,000 chemically defined compounds plus a large number of natural product extracts for anticancer activity since 1990 [1-3]
• Expression (microarray data) with bioinformatic strategies can use efficacy in one cell type to predict efficacy in cell types not in the panel in A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery however in Coombes, Wang and Baggerly in Genomic Signatures on the NCI60 cell lines DO NOT predict patient response to chemotherapy, and [5] where the authors could not reproduce the results in [4] and discussed in Putting Oncology Patients at Risk and a RETRACTED paper in [6] relying on miRNA signatures.

Even though the immunocompromised model has contributed greatly to the chemotherapeutic drug discovery process. using these models to develop the new line of immuno-oncology products has been met with challenges three which I highlight below with curated database of references and examples.

From a practical standpoint development of a mouse which can act as a recipient for human tumors yet have a humanized immune system allows for the preclinical evaluation of antitumoral effect of therapeutic antibodies without the need to use neutralizing antibodies to the comparable mouse epitope,   thereby reducing the complexity of the study and preventing complications related to pharmacokinetics.

Champions Oncology Files Patents for Use of PDX Platform in Immune-Oncology

Hackensack, NJ – August 17, 2015 – Champions Oncology, Inc. (OTC: CSBR), engaged in the development of advanced technology solutions and services to personalize the development and use of oncology drugs, today announced that it has filed two patent applications with the United States Patent and Trademark Office (USPTO) relating to the development and use of mice with humanized immune systems to test immune-oncology drugs and therapeutic cancer vaccines.

Dr. David Sidransky, the founder and Chairman of Champions Oncology commented, “Drug development ‎in the immune-oncology space is fundamentally changing our approach to cancer treatment. These patents represent potentially invaluable tools for developing and personalizing immune therapy based on cutting edge sequence analysis, bioinformatics and our unique in vivo models.”

Joel Ackerman, Chief Executive Officer of Champions Oncology stated, “Developing intellectual property related to our Champions TumorGraft® platform has been an important component of strategy. The filing of these patents is an important milestone in leveraging our research and development investment to expand our platform and create proprietary tools for use by our pharmaceutical partners. We continue to look for additional revenue streams to supplement our fee-for-service business and we believe these patents will help us capture more of the value we create for our customers in the future.”

The first patent filing covers the methodology used by the Company to create a mouse model, containing a humanized immune system and a human tumor xenograft, which is capable of testing the efficacy of immune-oncology agents, both as single agents and in combination with anti-neoplastic drugs. The second patent filing relates to the detection of neoantigens and their role in the development of anti-cancer vaccines.

Keren Pez, Chief Scientific Officer, explained, “In the last few years, there has been a significant increase in cancer research that focuses on exploring the power of the human immune system to attack tumors. However, it’s challenging to test immune-oncology agents in traditional animal models due to the major differences between human and murine immune systems. The Champions ImmunoGraft™ platform has the unique ability of mimicking a human adaptive immune response in the mice, which allows us to specifically evaluate a variety of cancer therapeutics that modulate human immunity.

“Therapeutic vaccines that trigger the immune system to mount a response against a growing tumor are another area of intense interest. The development of an effective vaccine remains challenging but has an outstanding curative potential. Tumors harbor mutations in DNA that result in the translation of aberrant proteins. While these proteins have the potential to provoke an immune response that destructs early-stage cancer development, often the immune response becomes insufficient. Vaccines can trigger it by proactively challenging the system with these specific mutated peptides. Nevertheless, developing anti-cancer vaccines that effectively inhibit tumor growth has been complicated, partially due to challenges in finding the critical mutations, among others difficulties. With the more recent advances in genome sequencing, it’s now possible to identify tumor-specific antigens, or neoantigens, that naturally develop as an individual’s tumor grows and mutates,” she continued.

Traumatic spinal cord injury in mice with human immune systems.

Carpenter RS, Kigerl KA, Marbourg JM, Gaudet AD, Huey D, Niewiesk S, Popovich PG.

Exp Neurol. 2015 Jul 17;271:432-444. doi: 10.1016/j.expneurol.2015.07.011. [Epub ahead of print]

Inflamm Bowel Dis. 2015 Jul;21(7):1652-73. doi: 10.1097/MIB.0000000000000446.

Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases.

Koboziev I¹, Jones-Hall Y, Valentine JF, Webb CR, Furr KL, Grisham MB.

Author information

Abstract

Animal models of disease have been used extensively by the research community for the past several decades to better understand the pathogenesis of different diseases and assess the efficacy and toxicity of different therapeutic agents. Retrospective analyses of numerous preclinical intervention studies using mouse models of acute and chronic inflammatory diseases reveal a generalized failure to translate promising interventions or therapeutics into clinically effective treatments in patients. Although several possible reasons have been suggested to account for this generalized failure to translate therapeutic efficacy from the laboratory bench to the patient’s bedside, it is becoming increasingly apparent that the mouse immune system is substantially different from the human. Indeed, it is well known that >80 major differences exist between mouse and human immunology; all of which contribute to significant differences in immune system development, activation, and responses to challenges in innate and adaptive immunity. This inconvenient reality has prompted investigators to attempt to humanize the mouse immune system to address important human-specific questions that are impossible to study in patients. The successful long-term engraftment of human hematolymphoid cells in mice would provide investigators with a relatively inexpensive small animal model to study clinically relevant mechanisms and facilitate the evaluation of human-specific therapies in vivo. The discovery that targeted mutation of the IL-2 receptor common gamma chain in lymphopenic mice allows for the long-term engraftment of functional human immune cells has advanced greatly our ability to humanize the mouse immune system. The objective of this review is to present a brief overview of the recent advances that have been made in the development and use of humanized mice with special emphasis on autoimmune and chronic inflammatory diseases. In addition, we discuss the use of these unique mouse models to define the human-specific immunopathological mechanisms responsible for the induction and perpetuation of chronic gut inflammation.

J Immunother Cancer. 2015 Apr 21;3:12. doi: 10.1186/s40425-015-0056-2. eCollection 2015.

Human tumor infiltrating lymphocytes cooperatively regulate prostate tumor growth in a humanized mouse model.

Roth MD¹, Harui A¹.

Author information

Abstract

BACKGROUND:

The complex interactions that occur between human tumors, tumor infiltrating lymphocytes (TIL) and the systemic immune system are likely to define critical factors in the host response to cancer. While conventional animal models have identified an array of potential anti-tumor therapies, mouse models often fail to translate into effective human treatments. Our goal is to establish a humanized tumor model as a more effective pre-clinical platform for understanding and manipulating TIL.

METHODS:

The immune system in NOD/SCID/IL-2Rγnull (NSG) mice was reconstituted by the co-administration of human peripheral blood lymphocytes (PBL) or subsets (CD4+ or CD8+) and autologous human dendritic cells (DC), and animals simultaneously challenged by implanting human prostate cancer cells (PC3 line). Tumor growth was evaluated over time and the phenotype of recovered splenocytes and TIL characterized by flow cytometry and immunohistochemistry (IHC). Serum levels of circulating cytokines and chemokines were also assessed.

RESULTS:

A tumor-bearing huPBL-NSG model was established in which human leukocytes reconstituted secondary lymphoid organs and promoted the accumulation of TIL. These TIL exhibited a unique phenotype when compared to splenocytes with a predominance of CD8+ T cells that exhibited increased expression of CD69, CD56, and an effector memory phenotype. TIL from huPBL-NSG animals closely matched the features of TIL recovered from primary human prostate cancers. Human cytokines were readily detectible in the serum and exhibited a different profile in animals implanted with PBL alone, tumor alone, and those reconstituted with both. Immune reconstitution slowed but could not eliminate tumor growth and this effect required the presence of CD4+ T cell help.

CONCLUSIONS:

Simultaneous implantation of human PBL, DC and tumor results in a huPBL-NSG model that recapitulates the development of human TIL and allows an assessment of tumor and immune system interaction that cannot be carried out in humans. Furthermore, the capacity to manipulate individual features and cell populations provides an opportunity for hypothesis testing and outcome monitoring in a humanized system that may be more relevant than conventional mouse models.

Methods Mol Biol. 2014;1213:379-88. doi: 10.1007/978-1-4939-1453-1_31.

A chimeric mouse model to study immunopathogenesis of HCV infection.

Bility MT¹, Curtis A, Su L.

Author information

Abstract

Several human hepatotropic pathogens including chronic hepatitis C virus (HCV) have narrow species restriction, thus hindering research and therapeutics development against these pathogens. Developing a rodent model that accurately recapitulates hepatotropic pathogens infection, human immune response, chronic hepatitis, and associated immunopathogenesis is essential for research and therapeutics development. Here, we describe the recently developed AFC8 humanized liver- and immune system-mouse model for studying chronic hepatitis C virus and associated human immune response, chronic hepatitis, and liver fibrosis.

PMID:

25173399

[PubMed – indexed for MEDLINE]

PMCID:

PMC4329723

Free PMC Article

• · Images from this publication.See all images (3)Free text

Immune humanization of immunodeficient mice using diagnostic bone marrow aspirates from carcinoma patients.

Werner-Klein M, Proske J, Werno C, Schneider K, Hofmann HS, Rack B, Buchholz S, Ganzer R, Blana A, Seelbach-Göbel B, Nitsche U, Männel DN, Klein CA.

PLoS One. 2014 May 15;9(5):e97860. doi: 10.1371/journal.pone.0097860. eCollection 2014.

From 2015 AACR National Meeting in Philadelphia

LB-050: Patient-derived tumor xenografts in humanized NSG mice: a model to study immune responses in cancer therapy Sunday, Apr 19, 2015, 3:20 PM – 3:35 PM Minan Wang1, James G. Keck1, Mingshan Cheng1, Danying Cai1, Leonard Shultz2, Karolina Palucka2, Jacques Banchereau2, Carol Bult2, Rick Huntress2. 1The Jackson Laboratory, Sacramento, CA; 2The Jackson Laboratory, Bar Harbor, ME

References

1. Paull KD, Shoemaker RH, Hodes L, Monks A, Scudiero DA, Rubinstein L, Plowman J, Boyd MR. J Natl Cancer Inst. 1989;81:1088–1092. [PubMed]
2. Shi LM, Fan Y, Lee JK, Waltham M, Andrews DT, Scherf U, Paull KD, Weinstein JN. J Chem Inf Comput Sci. 2000;40:367–379. [PubMed]
3. Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff A, et al. J Natl Cancer Inst. 1991;83:757–766. [PubMed]
4. Potti A, Dressman HK, Bild A, et al. Genomic signatures to guide the use of chemotherapeutics. Nat Med. 2006;12:1294–1300. [PubMed]
5. Baggerly KA, Coombes KR. Deriving chemosensitivity from cell lines: forensic bioinformatics and reproducible research in high-throughput biology. Ann Appl Stat. 2009;3:1309–1334.
6. Carlson, B. Putting Oncology Patients at Risk Biotechnol Healthc. 2012 Fall; 9(3): 17–21.
7. Salter KH, Acharya CR, Walters KS, et al. An Integrated Approach to the Prediction of Chemotherapeutic Response in Patients with Breast Cancer. Ouchi T, ed. PLoS ONE. 2008;3(4):e1908. NOTE RETRACTED PAPER

Other posts on this site on Animal Models, Disease and Cancer Include:

Heroes in Medical Research: Developing Models for Cancer Research

Guidelines for the welfare and use of animals in cancer research

Model mimicking clinical profile of patients with ovarian cancer @ Yale School of Medicine

Vaccines, Small Peptides, aptamers and Immunotherapy [9]

Immunotherapy in Cancer: A Series of Twelve Articles in the Frontier of Oncology by Larry H Bernstein, MD, FCAP

Mouse With ‘Humanized Version’ Of Human Language Gene Provides Clues To Language Development

The SCID Pig: How Pigs are becoming a Great Alternate Model for Cancer Research

The SCID Pig II: Researchers Develop Another SCID Pig, And Another Great Model For Cancer Research

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