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Posts Tagged ‘rigosertib’


Targeting KRAS Mutations In Pancreatic Tumours

Curator: David Orchard-Webb, PhD

 

In pancreatic cancer KRAS is mutated between 70-90%. Next generation sequencing suggests 90%, however it must be understood that the allelic frequency of KRAS mutation will not be 100% – not all the cells within the tumour will contain a KRAS mutation due to tumour heterogeneity [1]. Regardless of the exact figure KRAS mutation is more frequent in pancreatic ductal adenocarcinoma (PDAC) than in any other cancer and plays a role in cancer initiation and progression. The four most common KRAS mutations in PDAC are G12D > G12V > G12C > G13D [2]. The use of mutant RAS peptides as a cancer vaccine immunotherapy is an established concept and the nordic company Targovax has a RAS vaccine called TG01 in phase I/II clinical trials for pancreatic cancer.

 

Inhibiting the signalling activity of KRAS in pancreatic cancers is also attractive however failures most notably of the farnesyl transferase inhibitors in clinical trials has led to unwarranted pessimism. Two farnesyl transferase inhibitors have been tested and failed in clinical trials of pancreatic cancer, Tipifarnib (Johnson & Johnson), and L-778.123 (Merck & Co.) [3]. However farnesyltransferase inhibitors may still have a role in the treatment of a rare subset of pancreatic cancer patients. Importantly rare cases of complete response to farnesyltransferase inhibitors are known in pancreatic cancer patients [4]. Recently new drug targets that shut-down mutated RAS signalling have emerged.

 

Small molecule competitive binders of the prenyl-binding protein PDEδ have been developed by researchers at the Max Planck Institute of Molecular Physiology, Dortmund, Germany. RAS localisation to the membrane is essential for its signalling in cancer. RAS proteins are farnesylated and this modulates their localisation to the plasma membrane. The farnesyl tail of RAS is bound by PDEδ which facilitates its transport to the plasma membrane. A series of compounds with ever greater affinity for the PDEδ pocket that binds RAS have been synthesised. Deltazinone was their first generation compound and Deltarasin their second generation compound [5, 6]. The Dortmund group have shown in pancreatic cancer cell lines with mutated KRAS that these compounds reduce cell proliferation.

 

A new small molecule called Rigosertib has been developed by the laboratory of E. Premkumar Reddy (New York) and collaborators which binds to the RAS-binding domain (RBD) present in proteins that interact with RAS and thus block this interaction, nullifying activated RAS [7]. Rigosertib dramatically reduced the growth of human HCT116 colon cancer cell line implanted as a mouse xenograft. It also reduced the number of Pancreatic Intraepithelial Neoplasia (PanIN) lesions, precursors of PDAC, present in KRAS mutant mice.

 

It will be important to further refine these compounds into leads for preclinical development through to investigational new drug (IND) submission as they are very promising developments for RAS active tumours such as PDAC.

 

REFERENCES

 

  1. Lennerz, Jochen K., and Albrecht Stenzinger. ‘Allelic Ratio of KRAS Mutations in Pancreatic Cancer’. The Oncologist 20, no. 4 (2015): e8–e9. http://theoncologist.alphamedpress.org/content/20/4/e8.short.
  2. Stephen, Andrew G., Dominic Esposito, Rachel K. Bagni, and Frank McCormick. ‘Dragging Ras Back in the Ring’. Cancer Cell 25, no. 3 (March 2014): 272–81. doi:10.1016/j.ccr.2014.02.017.
  3. Orchard­-Webb D. 2015. Future Directions in Pancreatic Cancer Therapy. JOP. Journal of the Pancreas 16:249­-255.
  4. Ledford, Heidi. ‘Cancer Researchers Revisit “Failed” Clinical Trials’. Nature, 18 April 2013. doi:10.1038/nature.2013.12835.
  5. Zimmermann, Gunther, Björn Papke, Shehab Ismail, Nachiket Vartak, Anchal Chandra, Maike Hoffmann, Stephan A. Hahn, et al. ‘Small Molecule Inhibition of the KRAS-PDEδ Interaction Impairs Oncogenic KRAS Signalling’. Nature 497, no. 7451 (30 May 2013): 638–42. doi:10.1038/nature12205.
  6. Papke, Björn, Sandip Murarka, Holger A Vogel, Pablo Martín-Gago, Marija Kovacevic, Dina C Truxius, Eyad K Fansa, et al. ‘Identification of Pyrazolopyridazinones as PDEδ Inhibitors’. Nature Communications 7 (20 April 2016): 11360. doi:10.1038/ncomms11360.
  7. Athuluri-Divakar, Sai Krishna, Rodrigo Vasquez-Del Carpio, Kaushik Dutta, Stacey J. Baker, Stephen C. Cosenza, Indranil Basu, Yogesh K. Gupta, et al. ‘A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling’. Cell 165, no. 3 (21 April 2016): 643–55. doi:10.1016/j.cell.2016.03.045.

 

Other Related Articles Published In This Open Access Online Journal Include The Following:

 

https://pharmaceuticalintelligence.com/2016/04/23/mutations-in-ras-genes/

https://pharmaceuticalintelligence.com/2016/05/01/immune-system-stimulants-articles-of-note-pharmaceuticalintelligence-com/

 

 

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Mutations in RAS genes

Larry H Bernstein, MD, FCAP, Curator

LPBI

 

Novel Mechanism Targets “Undruggable” RAS Oncogenes

http://www.genengnews.com/gen-news-highlights/novel-mechanism-targets-undruggable-ras-oncogenes/81252643/

https://youtu.be/PUOKny18iro

Dr. Reddy discussing findings from new research on developing drugs toward RAS.

http://www.genengnews.com/Media/images/GENHighlight/fx111851571281.jpg

Mechanism of new research targeting previously undruggable RAS gene. [Cell, Volume 165, 21 April 2016]

 

For greater than 30% of human cancers, RAS genes are mutated and have been implicated as key tumor drivers—making them some of the most sought after cancer drug targets. However, the absence of any drug-binding pockets in the mutant RAS proteins has made drug development extremely difficult. Yet now, a new study from researchers at the Icahn School of Medicine at Mount Sinai has identified a new mechanism for targeting this important cancer gene.

Mutations in RAS genes—such as HRAS, KRAS, and NRAS—are frequently observed in many of the most common and lethal tumors, including cancers of the pancreas, lung, and colon. While scientists have made significant headway in understanding these mutations and their impact on cellular signaling, little headway has been made toward developing drugs that systematically target the RAS oncogenes. This lack of progress has led many in the field to label RAS an “undruggable” cancer gene.

The Mt. Sinai team identified what they believe to be the first small molecule able to simultaneously inhibit the different signaling pathways activated by RAS oncogenes. This compound called rigosertib or ON01910.Na, acts as a protein-protein interaction inhibitor that prevents binding between RAS and signaling proteins (including RAF, PI3K, and others) that drive a cell into a cancer cell.

“Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway,” the authors wrote. “We also find that rigosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling.”

The findings from this study were published recently in Cell through an article entitled “A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling.”

Additionally, the investigators performed structural experiments to confirm the mode of action for rigosertib and also demonstrated the potential for this targeted mechanism in the treatment of several RAS-driven cancers.

“This discovery is a significant breakthrough for the cancer field,” explained senior study author E. Premkumar Reddy, Ph.D., professor of oncological sciences at the Icahn School of Medicine at Mount Sinai. “Rigosertib’s mechanism of action represents a new paradigm for attacking the intractable RAS oncogenes. Our current focus is to use the information from our studies with rigosertib to design the next generation of small molecule RAS-targeting therapies, and we are excited to have recently identified several compounds which we think improve on the qualities of rigosertib.”

 

A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling

Sai Krishna Athuluri-Divakar, Rodrigo Vasquez-Del Carpio,….., Aneel K. Aggarwal, E. Premkumar Reddycorrespondence

  • Rigosertib binds to the RAS-binding domains (RBDs) of multiple RAS effectors
  • Binding of rigosertib to RAF-RBD inhibits RAS-RAF interaction and impairs the kinase
  • Rigosertib inhibits MEK-ERK pathway activated by growth factors and oncogenic RAS

Oncogenic activation of RAS genes via point mutations occurs in 20%–30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating new approaches to inhibit this oncogenic protein. Functional studies have shown that the switch region of RAS interacts with a large number of effector proteins containing a common RAS-binding domain (RBD). Because RBD-mediated interactions are essential for RAS signaling, blocking RBD association with small molecules constitutes an attractive therapeutic approach. Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that ribosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling.

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