LIVE 9/21 3:20PM to 6:40PM KINASE INHIBITORS FOR CANCER IMMUNOTHERAPY COMBINATIONS & KINASE INHIBITORS FOR AUTOIMMUNE AND INFLAMMATORY DISEASES at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston
http://www.discoveryontarget.com/
http://www.discoveryontarget.com/crispr-therapies/
Leaders in Pharmaceutical Business Intelligence (LPBI) Group is a
Media Partner of CHI for CHI’s 14th Annual Discovery on Target taking place September 19 – 22, 2016 in Boston.
In Attendance, streaming LIVE using Social Media
Aviva Lev-Ari, PhD, RN
Editor-in-Chief
http://pharmaceuticalintelligence.com
#BostonDOT16
@BostonDOT
KINASE INHIBITORS FOR CANCER IMMUNOTHERAPY COMBINATIONS
3:20 Chairperson’s Opening Remarks
Guido J.R. Zaman, Ph.D., Managing Director & Head of Biology, Netherlands Translational Research Center B.V. (NTRC)
3:25 FEATURED PRESENTATION: Inhibition of PI3K and Tubulin
Doriano Fabbro, Ph.D., CSO, PIQUR Therapeutics
The PI3K signaling pathway is frequently activated in tumors. PQR309 is a selective dual inhibitor of PI3K and mTOR (currently in Phase I) in cancer patients. The preclinical pharmacology and toxicology of PQR309 is presented, including its activity in lymphoma preclinical models. In addition, we elucidate structural factors defining the PI3K inhibitory activity and tubulin-binding of PQR309 derivatives.
- PQR309 & GDC0941 arrest cells i G1/S (typical for PI3K/mTOR Inhibitor)
- What drives Antiproliferative Activity of BKM120: PI3K or MT or both?
- BKM120 Binds to beta-Tubulin/alpha -Tubulin Interfere
- T2R-TTL complex
- Orientation of BKM120 in PI3K
- PQR309 – is a brain penetrating, PK and BAV by PO, good metabolic stability
- PQR309 ANti-proliferative in Lymphoma
- Clinical efficacy – Now in Phase II
4:05 Design and Development of a Novel PI3K-p110β/δ Inhibitor, KA2237 with Combined Tumor Immunotherapeutic, Growth Inhibition and Anti-Metastatic Activity
Stephen Shuttleworth, Ph.D., FRSC, CChem, CSO, Karus Therapeutics Ltd.
The design and development of KA2237, a novel and selective inhibitor of PI3K-p110β/δ, will be described. This molecule has clinical potential in the treatment of solid and hematological malignancies, through its direct inhibition of tumor growth and metastatic spread, and through immunotherapeutic mechanisms. Phase I studies for KA2237 are scheduled to commence in Q2 2016 at the MD Anderson Cancer Center.
- Design & Development of Novel, Oral, selective PI3K enzyme family: CLass I,II, III, IV based upon:
- Class I IA IB
- KA2237: DUal PI3K – p110beta/delta-selective inhibitor: CTL, Treg, p1 106 T sell response
- Molecular signature in the tumor
- WT p110delta, WT 1 10beta+, Mutant p1 10Beta+, PTEN-null, Ibrutinib-resistance, Growth inhibition; suppression of metastesis (p110beta
- small molecule combination agents: potential aided by selectivity over p110
- KA2237: clinical Pi3K-p110beta/delta Inhibitor- ATP -comtetitive
- Doxorubicin -cytotoxic control
- KA2237 superior activity to Idelasib
- KA2237 – suppression of micro-metastasis in 4T1 synergenic model
- Tumor Growth inhibition Pre-Surgery
- Tumor Re-Growth Inhibition Post-Surgery
- metastasis post surgery
- Tumor-free mice post-surgery
- CHemistry: IHC -pAKT; IHC – FOxp3+
- KA2237 inhibits HGF-stimulated 4T1 tumor
- 2004 – Preclinical develpemnt PI3K is reported
- 2006 First PI#K is enter Clinical Trials
- Targeting p1110Beta (PIKeCB) mutations in cancer with KA2237
- DIscovery of the mutations lead drug discovery
- KA@@#&: Potential in treatment of B-Cell Lymphom AS IN TARGETING IBRUTINIB RESISTENCE
- GROWTH INHIBITION IN HEMATOLOGICAL CANCERS TUMOE CELL LINE PANEL
- KA2237 – differentiated from competing Pi3K is Superior efficacy cf. p110delta
- Combination: Not histone deacetylase but a tubulin deacetylase – Hsp90 ans Hsp70
- T cell exhausion: Tumor growth inhibition vs Suppression of lung metastasis
- Tumor BiologyRationale vs Clinical Agents
- Oncogenic mutants, solid tumor supression magrophage, combination PD-1, CTLA$
- FDA -approved kinase inhibitors
Summary
- phase I clinical study commenced in pathients with B cell Lymphoma
- Potential for treatment of solid and hematological malignancies
4:35 InCELL Pulse: A Novel Cellular Target Engagement Assay Platform for Drug Discovery
Daniel Treiber, Ph.D., Vice President, KINOMEscan, DiscoverX Corporation
InCELL Pulse is a quantitative and rapid method for measuring cellular target engagement potencies for small molecule inhibitors. InCELL Pulse capitalizes on two novel DiscoverX technologies, Enzyme Fragment Complementation (EFC) and Pulse Denaturation, which overcome the limitations of related target engagement methods. Examples across multiple target classes will be described.
- InCELL Pulse – cellular Target ENgagement Assays
- cellular thermal stabilization-based approach
- simple, rapid and generig cellular alternative to CETSa
- Thermal melting Curves vs Isothermal Inhibitor EC50 curves
- Pulse Denaturation compound binding, or not binding
- ABL1 Tyrosine Kinase – dose response curve – allosteric Inhibitor
- MTH1 Hydrolase: InCELL Pulseassay validated for multiple substrate-competitive inhibitors
- Validated InCELL Pulse Assays for Diverse Kinases
- Kinase targets; BRAF, MEC1
Summary
- validation across proteins
4:50 Potential Application of Fluorescence Lifetime Assays to Enable Robust, Rapid Protein Binding Assays
Paul Wylie, Ph.D., Head, Applications, TTP Labtech
Current methods to screen protein binding interactions often have limitations due to the reliance on antibodies, but also interference from fluorescent molecules. Fluorescence lifetime has the potential to overcome these problems through directly labelled proteins and lifetime measurements that are independent of total fluorescence intensity.
- Protein binding as a target class
- protein-protein interactions (PPIs)
- FRET/HTRF
- FP
- AlphaScreen
What new in FLT?
- long lifetime fluorophores, economical reagent platform
- directly labelled reagents – no antibodies
- independent of total intensity – reduced interference
- robustness screen vs nuisance screen – caspase-3
- productive; reduction false positives: FRET
- protein-binding assays & FLT formats:
- protein – small molecule binding – CECR2
- protein – peptide binding: long and sholt lifetime
- Site-specific labelling vs Non-selective labelling
- Toolbox for PoC
- Detection reagents
- Further develop technology
5:05 Refreshment Break in the Exhibit Hall with Poster Viewing
6:40 End of Day
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