Original Agenda
We are actively working with our speakers to confirm their availability for the virtual event. Initial response from our speakers has been very positive, and we are optimistic we will have the new programs ready to share here soon.

Cambridge Healthtech Institute’s 13th Annual

Kinase Inhibitor Discovery

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

September 17 - 18, 2020

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

11:20 am Conference Registration for Part B Programs


12:20 pm Event Chairperson's Opening Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target 2020, Cambridge Healthtech Institute
12:30 Plenary Keynote Introduction (Sponsorship Opportunity Available)

Tackling Undruggable Oncoproteins: Lessons from the VHL Tumor Suppressor Protein

William G. Kaelin, Jr., MD, Professor and Investigator, Howard Hughes Medical Institute, Oncology, Dana-Farber Cancer Institute

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.


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
Anthony A. Philippakis, PhD, Chief Data Officer, Data Sciences & Data Engineering, Broad Institute; Venture Partner, GV
Andrew Plump, MD, PhD, President, Research & Development, Takeda Pharmaceuticals, Inc.
2:00 Close of Plenary Keynote Program
2:00 Dessert Break in the Exhibit Hall with Poster Viewing


2:45 Organizer's Welcome Remarks

Cambridge Healthtech Institute

2:50 Chairperson's Remarks

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

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.


3:25 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.

Raghava Reddy Kethiri, PhD, CSO, Laxai Life Sciences Pvt. Ltd.
4:10 Sponsored Presentation (Opportunity Available)
4:25 Refreshment Break in the Exhibit Hall with Poster Viewing
5:00 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.


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

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

HER2-targeted tyrosine kinase inhibitors (TKIs), such as neratinib and lapatinib, 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.


Discovery of Potent TTBK1 Inhibitors that Lower Tau Phosphorylation in vivo for the Treatment of Alzheimer’s Disease

Toma Halkina, Medicinal Chemistry, Drug Discovery, Biogen

Hyperphosphorylated tau is the primary component of neurofibrillary tangles, a hallmark pathology associated with Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Tau tubulin kinase 1 (TTBK1) is a CNS-specific enzyme that phosphorylates tau at pathologically relevant sites. Several studies have linked TTBK1 activity with neurodegenerative disease, and it has been proposed that inhibition of TTBK1 with an ATP-competitive small molecule might be a viable therapeutic approach for the treatment of AD and other tauopathies. The starting point of our structure-based design optimization approach was a known NIK inhibitor, which was reported to have activity against TTBK1. Structural analysis of an in-house crystal structure of this compound bound to the kinase domain of TTBK1 led to the discovery of a novel series of azaindole and azaindazole TTBK1 inhibitors. Optimization of the potency, kinome selectivity, and ADMET properties of our initial hits led to the identification of several tool compounds with a suitable profile for in vivo proof of pharmacology experiments. Acute treatment with these compounds resulted in a dose-dependent decrease of tau phosphorylation at pathologically relevant sites in mice. A correlation between target engagement and inhibition of tau phosphorylation using a chemoproteomics platform was also established and will be discussed.

6:30 Dinner Short Course Registration (Premium Package or separate registration required)
7:00 Dinner Short Courses 10-12 (see Short Courses page for details)
9:30 Close of Day

Friday, September 18

7:00 am Registration
7:30 Interactive Breakfast Breakout Discussion Groups
Grab a cup of coffee 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. Visit the conference website for discussion topics and moderators.
8:30 Transition to Sessions


8:40 Chairperson's Remarks

Istvan Enyedy, PhD, Director, Computational Chemistry, Black Diamond Therapeutics


Interaction of Substrates and Inhibitors with Tousled-Like Kinases

Benjamin Turk, PhD, Associate Professor, Pharmacology, Yale School of Medicine

Tousled-like kinases (TLK1/2) are nuclear kinases that function in genome maintenance by phosphorylation of histone chaperone proteins. Loss of TLK2 substantially impairs proliferation of some tumor cell lines, suggesting it may constitute a new therapeutic target in cancer. We discuss efforts to identify small-molecule inhibitors of TLK2 and describe an unusual binding mode that enforces selectivity for its target substrates.


Checkpoint Inhibition of Abl Kinase Can Functionally Reverse Neurodegenerative Disease

Milton Werner, President & CEO, Inhibikase Therapeutics, Inc.

Parkinson’s Disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with more than 15,000,000 cases worldwide. PD arises from a toxic form of alpha-synuclein. Mounting evidence argues that the cellular Abelson tyrosine kinase (c-Abl) acts as a checkpoint along the pathway to disease, and that chemical modification of dysfunctional alpha-synuclein is necessary to create the toxic form leading to pathology.  Activation of c-Abl, but not aggregation and misfolding of alpha-synuclein per se, is necessary and sufficient to initiate neurodegeneration in PD. C-Abl inhibition can suppress these events and may lead to functional reversal of disease.


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.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

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.


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.

11:55 Sponsored Presentation (Opportunity Available)
12:25 pm Session Break
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:05 Refreshment Break in the Exhibit Hall with Poster Viewing


1:50 Chairperson's Remarks

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

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

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.


Degradation of Important Oncology Targets via PROTACs: TrkC and CDK4/6

Kevin Burgess, PhD, Rachal Professor of Chemistry, Texas A&M University

PROTACs will draw an E3 ligase and the protein target into proximity to deliver ubiquitin to the target, if there is a synergistic binding between the two proteins; that ubiquitinylation will cause degradation of the target protein in the proteasome. This talk describes PROTACs we have formed for two target proteins: TrkC and CDK4/6. We will explain why these proteins are important, why degradation (or inhibition) of CDK4/6 is desirable, but insufficient for chemotherapy, and our strategy to attempt to work around this. Also covered will be some of our work on “tumor-seeking cyanine dyes” conjugated to kinase inhibitors.


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 for targeting these functions. 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.

3:55 Close of Conference

Choose 2 Short Courses and 2 Conferences/Training Seminars
Sept. 15 Short Course: SC4: Biochemistry and Pharmacology of the Ubiquitin-Proteasome System
Sept. 16-17 Conference: PROTACs and Targeted Protein Degradation – Part 1
Sept. 17 Dinner Short Course: SC11: Insights into PROTACs and Targeted Protein Degradation
Sept. 17-18 Conference: Kinase Inhibitor Discovery