Cambridge Healthtech Institute’s 13th Annual

Kinase Inhibitor Discovery

Emerging Targets, New Tools and Strategies, and Targeted Kinase Degraders

September 17 - 18, 2020 ALL TIMES EDT

Kinase inhibitor discovery is a very active area as developers are exploring more deeply into designing immune-modulatory agents as single or combination therapies, tackling chronic disease indications such as inflammation and CNS disorders, as well as effectively harnessing allosteric modulators, and covalently binding compounds. This year we will also be discussing the role of artificial intelligence, new and non-oncology drug targets, phosphatases, and protein degraders in kinase development. Cambridge Healthtech Institute’s 13th Annual Kinase Inhibitor Discovery conference will once again bring together academic and industry leaders to network, collaborate and discuss advances in kinase inhibitor discovery and development.

Thursday, September 17

PLENARY KEYNOTE PROGRAM

12:20 pm

PLENARY KEYNOTE: Tackling Undruggable Oncoproteins: Lessons from the VHL Tumor Suppressor Protein

William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics

VHL tumor suppressor protein (pVHL) inactivation is common in kidney cancer and upregulates the HIF2 transcription factor. PT2977/MK-6482 is an allosteric HIF2 inhibitor now in Phase 3 testing. Thalidomide-like drugs (IMiDs) bind to cereblon which, like pVHL, is the substrate-binding unit of a ubiquitin ligase. IMiDs redirect cereblon to destroy the myeloma oncoproteins, IKZF1 and IKZF3. We have developed new assays for identifying drugs that can destabilize oncoproteins of interest.

12:45 pm LIVE Q&A:

Plenary Keynote Discussion

Panel Moderator:
Stewart Fisher, PhD, CSO, C4 Therapeutics, Inc.
Panelist:
William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics
12:55 pm LIVE PANEL AND Q&A:

Plenary Keynote Discussion: De-Risking Early Drug Discovery

Panel Moderator:
Nadeem Sarwar, PhD, Founder & President, Eisai Center for Genetics Guided Dementia Discovery, Eisai, Inc.
  • Data Sciences
  • ​Novel Chemical Modalities
  • Investment and Partnering Models
  • COVID-19 Progress as Examples of Successful Partnerships
Panelists:
Anthony A. Philippakis, PhD, Chief Data Officer, Data Sciences & Data Engineering, Broad Institute; Venture Partner, GV
Stephen A. Hitchcock, PhD, Head, Research, Takeda Pharmaceuticals, Inc.
1:35 pm Lunch Break - View Our Virtual Exhibit Hall

KINASE INHIBITOR DISCOVERY - AN OVERVIEW

Guido Zaman, PhD, Managing Director and Head of Biology, NTRC

Recent highlights in the development of new kinase inhibitor drugs will be presented, including recently approved FGFR, BTK, CSF1R, and TRK inhibitors. The full kinome profiles of all 62 kinase inhibitor drugs approved for cancer were determined on 300 kinases. Target residence time was studied with a panel of 100 kinases binding assays using Biacore. Cancer cell-panel profiling on Oncolines led to the discovery of novel drug response biomarkers.


INFORMATICS AND AI FOR KINASE DISCOVERY

2:25 pm Automation and Artificial Intelligence in Kinase Inhibitor Discovery
Istvan Enyedy, PhD, Director, Black Diamond Therapeutics

Traditional drug discovery is based on sequentially using approaches to optimizing compounds. Cloud computing, machine learning, and automation allow us to use several approaches in parallel to quickly cover a large chemical space in search of the best compound to modulate the activity of the kinase of interest. The talk will show the implementation of these approaches in ORION.


2:45 pm Uncovering Novel Therapeutic Opportunities within the Dark Kinome
Shawn M. Gomez, Eng Sc D, Professor, Joint Department of Biomedical Engineering & Pharmacology, University of North Carolina at Chapel Hill

Nearly all aspects of cellular signaling are touched by the kinome, with dysregulation of this network a key driver of disease. In this talk, I'll describe recent work focused on characterizing the architecture of the kinome, along with its response to targeted perturbations. With particular emphasis on poorly studied "dark kinases", this work includes new experimental efforts to quantify kinome behavior in response to targeted drug perturbations, along with newly developed machine learning approaches that greatly enhance our ability to identify novel druggable targets.

3:05 pm Sponsored Presentation (Opportunity Available)
3:25 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Guido Zaman, PhD, Managing Director and Head of Biology, NTRC
Panelists:
Shawn M. Gomez, Eng Sc D, Professor, Joint Department of Biomedical Engineering & Pharmacology, University of North Carolina at Chapel Hill
Istvan Enyedy, PhD, Director, Black Diamond Therapeutics
3:45 pm Happy Hour - View Our Virtual Exhibit Hall
4:15 pm Close of Day

Friday, September 18

NON-ONCOLOGY INDICATIONS AND UNDERSTUDIED KINASES

10:00 am

Profiling HER2-Targeted Tyrosine Kinase Inhibitors to Identify Novel Treatment Indications

Neil Conlon, Postdoctoral Fellow, National Institute for Cellular Biotechnology, Dublin City University

HER2-targeted tyrosine kinase inhibitors (TKIs), such as lapatinib, tucatinib and neratinib, have shown excellent clinical activity in HER2-positive breast cancer. However, the effectiveness of these drugs has been limited in other cancer types. Our study examined these HER2-targeted TKIs in a large-scale cell line analysis in order to determine novel biomarkers of response to these drugs, and discover new potential indications.

10:20 am

Targeting BRAFV600E Dimers Using an Allosteric Site

Evris Gavathiotis, PhD, Professor, Biochemistry, Albert Einstein College of Medicine

BRAF kinase is a critical effector of the MAPK/ERK signaling pathway that is hyperactivated in several cancers, including melanoma, colorectal, and thyroid. FDA-approved RAF inhibitors poorly inhibit BRAF dimers, leading to tumor resistance. Through a cell-based screening assay, crystal structures, and structure-based drug design, we identified novel inhibitors that use an allosteric site. We will present a novel class of BRAF dimer selective inhibitors that use this allosteric site.

10:40 am

Structure-Based Design and Synthesis of Novel PRPF4B Kinase Inhibitors as Chemical Probes for Target Validation

Hatylas Azevedo, PhD, MBA, R&D Manager, Drug Discovery, Aché Laboratórios

Pre-mRNA Processing Factor 4 (PRPF4) is a kinase previously associated with splicing regulation and triple-negative breast cancer metastasis formation in vivo, although it remains largely understudied. Using this compound as a starting point, several analogues were synthesized aiming at maintaining high potency while further increasing selectivity and cell permeability. Compounds were tested in the differential scanning fluorimetry, MDCK permeability, and 320-kinase selectivity assays. The best compounds exhibited high potency with relevant gains in cell permeability and selectivity. Further optimization is ongoing to attenuate the activity against some kinase off-targets. The co-crystal structure between one of the analogues and PRPF4 was obtained to rationalize the next cycles of design by exploring unique interactions between the ligand and kinase hinge residues.

11:00 am

Dual Targeting of Mutant EGFR Kinase with ATP-Site and Allosteric Inhibitors

Tyler Beyett, PhD, Research Fellow, Dana-Farber Cancer Institute and Harvard Medical School

Mutations in the epidermal growth factor receptor (EGFR) are a major driver of non-small-cell lung cancer. We developed mutant-selective allosteric inhibitors to combat acquired resistance to ATP-competitive drugs. Select allosteric inhibitors simultaneously and cooperatively bind with a subset of ATP-site inhibitors as confirmed by structural and biochemical studies. Such inhibitor combinations synergize in vivo, overcoming clinically relevant resistance mutations and delaying the emergence of additional mutations.

11:20 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Istvan Enyedy, PhD, Director, Black Diamond Therapeutics
Panelists:
Evris Gavathiotis, PhD, Professor, Biochemistry, Albert Einstein College of Medicine
Neil Conlon, Postdoctoral Fellow, National Institute for Cellular Biotechnology, Dublin City University
Tyler Beyett, PhD, Research Fellow, Dana-Farber Cancer Institute and Harvard Medical School
Hatylas Azevedo, PhD, MBA, R&D Manager, Drug Discovery, Aché Laboratórios
11:40 am Coffee Break - View Our Virtual Exhibit Hall

TARGETED KINASE DEGRADATION

11:55 am

Chemoproteomic Approaches to Interrogate the Degradable Kinome

Fleur Ferguson, PhD, Research Fellow, Biological Chemistry & Molecular Pharmacology, Dana-Farber Cancer Institute

Targeted protein degradation has rapidly gained traction as a promising therapeutic approach. Despite this, relatively little is understood about the factors governing a target's propensity for ubiquitination and degradation by specific E3-ligases, and the influence of chemical and cell type-specific variables on the effects of a given degrader molecule. We employed a chemo-proteomic approach to systematically characterize the factors that influence endogenous kinase degradation in different cellular contexts, profiling a library of well-characterized, diverse kinase degraders using a quantitative global proteomics approach.

Jian Jin, PhD, Mount Sinai Endowed Professor in Therapeutics Discovery; Professor, Departments of Pharmacological Sciences & Oncological Sciences; Director, Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai

The Jian Jin Laboratory at Mount Sinai is a leader in developing novel small-molecule degraders targeting oncogenic proteins. Our recent progress in this area, including discovery of first-in-class EZH2 and MEK1/2-selective degraders, will be presented. 

12:35 pm Sponsored Presentation (Opportunity Available)
12:55 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Fleur Ferguson, PhD, Research Fellow, Biological Chemistry & Molecular Pharmacology, Dana-Farber Cancer Institute
Panelists:
Jian Jin, PhD, Mount Sinai Endowed Professor in Therapeutics Discovery; Professor, Departments of Pharmacological Sciences & Oncological Sciences; Director, Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai
Rishi Shah, PhD, Senior Scientist, Medicine Design, GSK
1:15 pm Refresh Break - View Our Virtual Exhibit Hall
1:25 pm Brown Bag Lunch and Interactive Breakout Discussions - View Our Virtual Exhibit Hall

Grab your own lunch and join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Discussion topics and moderators will be listed on the website.


BREAKOUT: Advances in Structural Biology for Drug Discovery and Development

Tyler Beyett, PhD, Research Fellow, Dana-Farber Cancer Institute and Harvard Medical School
  • Emergence of cryo-electron microscopy
  • Advances in membrane protein crystallography
  • Application of computational methods to challenging targets

TARGETED KINASE DEGRADATION (CONT.)

2:00 pm

Hi-JAK-ing the Ubiquitin System: The Design and Physicochemical Optimisation of JAK PROTACs

Rishi Shah, PhD, Senior Scientist, Medicine Design, GSK

This talk outlines the design, physicochemical optimisation, and biological activity of a set of novel PROTACs targeting the JAK family of proximal membrane-bound proteins. JAK PROTACs from two distinct chemotypes were designed, optimising the physicochemical properties for each template to enhance cell permeation. These PROTACs are capable of inducing significant JAK1/JAK2 degradation, demonstrating an extension of the PROTAC methodology to an unprecedented class of protein targets and their mechanisms of action.

PROTACS: OPTIMIZING PHYSICOCHEMICAL PROPERTIES

2:20 pm

Using PROTAC Technology to Overcome On-Target Drug Toxicity: The Story behind DT2216

Daohong Zhou, MD, Professor, Department of Pharmacodynamics, College of Pharmacy, University of Florida at Gainesville

The on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce this toxicity, we converted ABT263 into DT2216, a BCL-XL PROTAC that targets BCL-XL to VHL for degradation. DT2216 was more potent against cancer cells, but less toxic to platelets than ABT263, because VHL is poorly expressed in platelets. This demonstrates the use of PROTACs to reduce on-target drug toxicities.

2:40 pm

Acquired Resistance to BET-PROTACs Caused by Genomic Alterations in Core Components of E3 Ligase Complexes

Lu Zhang, PhD, Senior Scientist, Cancer Biology, Oncology Discovery, AbbVie Inc.

With PROTACs progressing rapidly towards therapeutic applications, it is important to understand whether and how resistance to these novel agents may emerge. Using BET-PROTACs as a model system, we demonstrate that resistance to both VHL- and CRBN-based PROTACs was primarily caused by genomic alterations that compromise core components of the relevant E3 ligase complexes. This study reveals a novel resistance mechanism distinct from current targeted therapies and warrants future investigations.

3:00 pm Close of Conference





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