Cambridge Healthtech Institute’s 11th Annual
Kinase Inhibitor Chemistry
Emerging Targets, New Tools and Strategies, and Targeted Kinase Degraders
NEW DATES - AUGUST 25-26, 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 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 11th Annual Kinase Inhibitor Chemistry conference will once again bring together academic and industry leaders to network, collaborate, and discuss advances in kinase inhibitor discovery and development.
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Tuesday, April 14
7:00 am Registration Open and Morning Coffee
8:00 Welcome Remarks
Nandini Kashyap, Conference Director, Cambridge Healthtech Institute
8:05 Chairperson’s Opening Remarks
Felix Gonzalez Lopez de Turiso, PhD, Team Leader, Medicinal Chemistry, Drug Discovery, Biogen
8:10 Discovery of Brain-Penetrant ASK1 Inhibitors for the Treatment of Neurological Diseases
Felix Gonzalez Lopez de Turiso, PhD, Team Leader,
Medicinal Chemistry, Drug Discovery, Biogen
ASK1 is one of the key mediators of the cellular stress response and modulation of this pathway with the ATP-competitive inhibitor, Selonsertib, is being tested in the clinic for the treatment of liver fibrosis. To test the therapeutic value of
inhibiting ASK1 in neurological disease, we have identified novel ASK1 brain-penetrant inhibitors using a structure-based drug design approach. The results from this effort will be presented.
8:40 Targeted Therapy in Patients with PIK3CA-Related Overgrowth Syndrome
Guillaume Canaud, MD, PhD, Professor of Medicine, Hospital Necker Enfants Malades, Paris
PIK3CA-related overgrowth syndromes (PROS) are genetic disorders that result from somatic gain-of-function mutations of the PIK3CA gene. PROS has no specific treatment. We created the first mouse model of PROS that recapitulates the human disease
and demonstrated the efficacy of BYL719, PIK3CA inhibitor. On the basis of these results, we used BYL719 to treat 19 patients with PROS. The drug improved the disease symptoms in all patients and was not associated with any substantial side
9:10 Interfering with the Immune System: DMXD-011, a Potential Treatment for Systemic Lupus Erythematosus (SLE)
Trevor Perrior, MA, PhD, FRSC, CEO, Domainex Limited
Diseases arising from dysfunction of interferon signaling cause serious morbidity, can be life-threatening, and are poorly treated by existing medicines. The kinases, IKK-epsilon and TBK1, are key mediators of the production of pro-inflammatory
cytokines and Type 1 interferons. I will outline the fragment-based drug design of DMXD-011, a selective inhibitor of these two kinases, and describe its preclinical profile to illustrate why we believe this is a potential new treatment
for SLE and other interferonopathies.
9:40 Networking Coffee Break
10:05 Comprehensive Evaluation of CDK Inhibitor Landscape in Cells
Carrow Wells, Research Associate, Eshelman School of Pharmacy, University of North Carolina at Chapel
Although CDK inhibitors have proven to be therapeutically important, many CDK inhibitors lack family-wide profiling. To address this gap, we evaluated known CDK inhibitors against the full panel of cellular CDK assays. Utilizing the NanoBRET
assay platform, we identified selective and potent CDK inhibitors, as well as broadly active compounds which can aid in the design of new CDK inhibitors and our ability to match a kinase to a phenotype.
10:35 CDKs: Core Regulators of Transcription and Emerging Targets in Cancer Therapeutics
Pabitra Parua, PhD, Research Fellow, Robert P. Fisher Lab, Department of Oncological Sciences,
Icahn School of Medicine at Mount Sinai
Cyclin-dependent kinases (CDKs) regulate the cell-division and RNA polymerase II-dependent transcription cycles. Transcriptional CDKs have recently emerged as potential therapeutic targets in cancer, but deeper understanding of their functions
and interactions is needed to guide new drug discovery and development. Through chemical genetics, we identified novel substrates of a transcriptional CDK, Cdk9, and uncovered distinct Cdk9-phosphatase switches that govern key transitions
at the beginning and end of the transcription cycle.
11:05 Application of Large-Scale FEP Simulations for Lead Optimization
Tara Mirzadegan, PhD, Senior Director, US Head of Computational Chemistry, Janssen Pharmaceutical
Companies of Johnson & Johnson
Application of binding free energy using Free Energy Perturbation (FEP) against several projects will be discussed. This rigorous method requires extended simulation times, but recent advances in graphics processing units (GPUs) and both cluster-
and cloud-based computing have made possible the use of this method to prioritize large numbers of molecules. We will discuss the application of large-scale FEP+ experiment against a kinase target.
11:35 Session Break
11:45 LUNCHEON PRESENTATION: Sensors for Continuous Monitoring of Protein Kinase & Phosphatase Activity
Erik Schaefer, President, AssayQuant Technologies
AssayQuant® has combined chelation-enhanced fluorescence, using the sulfonamido-oxine (Sox) chromophore, with high-throughput peptide synthesis methods to identify optimized physiologically-based substrates for measuring the activity of
protein kinases and phosphatases. The result is a simple yet powerful method that allows continuous, quantitative and homogenous detection of activity using recombinant enzymes or crude cell or tissue lysates. This approach provides a
quantum improvement in assay performance and productivity needed to accelerate discovery and drug development efforts.
12:30 Session Break
1:15 Chairperson’s Remarks
Istvan J. Enyedy, PhD, Principal Scientist, Biogen
1:20 High-Resolution Structure and Inhibition of a Neuropsychiatric Disorder Linked Pseudokinase ULK4
Susmita Khamrui, PhD, Post-Doctoral Fellow, Pharmacological Sciences, Icahn School of Medicine at Mont Sinai Hospital
ULK4, a pseudokinase with some unusual mutations in the kinase catalytic motif, has genetically been linked to some neuropsychiatric disorders like schizophrenia. The first crystal structure of the human ULK4 kinase at high resolution will
be discussed here. ULK4 has no apparent phosphotransfer activity, but can bind to ATP in a Mg2+ independent manner. A virtual, as well as an experimental, screening was performed to identify small molecule binders of ULK4.
1:50 Machine Learning Models for Optimizing Brain Penetrant Kinase Inhibitors
Istvan J. Enyedy, PhD, Principal Scientist, Biogen
The design of kinase inhibitors for neurological indications is challenging because of limits in physicochemical properties that compounds should have in order to be brain penetrant. Models were developed for predicting P-gp- and BCRP-mediated
efflux and Kpuu. The talk will overview the performance of these models and the physicochemical properties that brain penetrant kinase inhibitors have.
2:20 Discovery of New Vaccinia-Related Kinase (VRK) Inhibitors as Chemical Probes for Target Validation
Hatylas Azevedo, PhD, MBA, R&D Manager, Drug Discovery, Aché Laboratórios
The vaccinia-related kinases 1and 2 (VRK1 and VRK2) were recently associated with poor prognosis, tumor growth and metastasis. The development of chemical probes with appropriate potency and selectivity is a key step to validate their role
in cancer and confirm the findings from siRNA or CRISPR/Cas9-based experiments. In this talk, it will be presented the efforts to develop new chemical probes for VRK1 and VRK2 using structure-based drug design approaches.
2:50 Targeting CDK Protein by Covalent Inhibitor and PROTAC Degrader
Tinghu Zhang, Scientist, Nathanael Gray Lab, Cancer Biology, Dana-Farber Cancer Institute/Harvard Medical School
This talk will discuss following about the second generation of CDK7 covalent inhibitor YKL5-124; selective inhibiting CDK12/13 by covalent inhibitor; discovery of first CDK9 degrader with a pan CDK binder SNS032; and selective degrade CDK4
and CDK6 with PROTAC technology.
3:20 SAR by Space: Enriching BRD4 Inhibitor Hit Sets from the Chemical Space
Franca Klingler, PhD, Head, Discovery Services, BioSolveIT
We introduce SAR by Space, a concept to drastically accelerate SAR elucidation. Hits from the REAL Space were combi-docked into the binding site of BRD4, thus avoiding time-consuming simulations. Five micromolar hits have been synthesized,
and verified within less than 6 weeks, including the measurement of IC50 values.
3:35 Refreshment Break in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)
4:35 Plenary Welcome Remarks from Event Director with Poster Finalists Announced
Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute
4:45 Plenary Technology Spotlight: Accelerating Drug Discovery from Hit Finding to Candidate Selection with Physics and Machine Learning-Based Calculations
Repasky, PhD, Vice President, Life Sciences Products, Schrödinger
The impact of the Schödinger computational platform in drug discovery is illustrated using recent case studies from internal and collaborative discovery projects. The Platform facilitates halving the number of synthesized
molecules and time to candidate relative to industry standards. Key elements of the Platform are described including Free Energy Perturbation to accurately predict relative protein-ligand binding, machine learning to generate
and rapidly assess millions of ideas, and collaborative sharing of project information through LiveDesign.
5:10 Plenary Keynote Introduction (Sponsorship Opportunity Available)
5:15 PLENARY KEYNOTE:
Medicinal Chemistry: Where Are We Headed?
Wendy Young, PhD, Senior Vice President, Small Molecule Discovery, Genentech
Major shifts in the way medicinal chemists discover novel medicines have evolved over the past few decades. Technological advances have significantly increased the ability to triage compound design and synthesize compounds faster. New
approaches in structural biology have enhanced our ability to visualize molecules and their corresponding binding sites. Drug discovery teams have moved from local to global and our deepened understanding of biology has extended our
reach. This lecture will explore past trends in drug discovery, current status of the industry, and the future of medicinal chemistry.
6:00 Welcome Reception in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)
7:00 Close of Day
Day 1 | Day 2 | Download Brochure
Wednesday, April 15
7:30 am Continental Breakfast Breakout Discussions - View All Breakouts
In this session, attendees fill their plate from the breakfast buffet and then choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small-group
format allows participants to informally meet potential collaborators, share examples from their work, and discuss ideas with peers.
Topic: Artificial Intelligence in Kinase Drug Discovery and Development
Moderator: Istvan J. Enyedy, PhD, Principal Scientist, Biogen
- Use of AI in kinase inhibitor drug design and optimization
- Pros and cons of AI in drug discovery
- What is a novel kinase inhibitor and how can we expand the chemical space of kinase inhibitors?
Topic: Kinase Inhibitors Moving beyond Cancer Therapy
Moderator: Carrow Wells, Research Associate, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Chronic dosing
- CNS kinase targets
- BBB penetration and selectivity
Topic: The Future of Kinase Inhibitors
Moderator: Hatylas Azevedo, PhD, MBA, R&D Manager, Drug Discovery, Aché Laboratórios
- Allosteric inhibitors
- Artificial intelligence
- Different scaffolds (natural products, macrocycles, covalent inhibitors)
8:30 Chairperson’s Remarks
Philip Chamberlain, DPhil, Executive Director, Structural and Chemical Biology, Celgene
8:35 New Activities for Cereblon Modulators
Philip Chamberlain, DPhil, Executive Director, Structural and Chemical Biology,
Cereblon can be redirected to degrade neo-substrate proteins using low-molecular-weight small molecules. An understanding of the structural basis of substrate recruitment has enabled the discovery of new neo-substrates, including proteins
that lack canonical small-molecule binding sites.
9:05 So Many Ubiquitin Ligases and So Few PROTACs: Carving a New Path with Novel Ligases
Tauseef Butt, PhD, President and CEO, Progenra Inc.
PROTAC field is at its infancy. Only the well-known ligases (Cereblon, VHL, HDM2 and cIAPs) have been exploited by medicinal chemists. Too many resources are devoted to these ligases as vehicles for PROTACs. Progenra has focused its attention
to novel ubiquitin ligases and discovered an entirely new class of PROTACs. We have validated applications of novel ligases by designing PROTACs with promiscuous kinase inhibitor that degrades a number of kinases not degraded by traditional
ligase PROTACs. Kinetics and dose response has established their application in oncology, inflammatory and neuroscience.
9:35 Coffee Break in the Exhibit Hall with Poster Awards Announced
Poster Awards Sponsored by Enamine Ltd
10:30 Molecular Mechanisms of Small Molecule-Mediated Ubiquitin Ligase Targeting
Eric Fischer, PhD, Assistant Professor, Cancer Biology/ Biological Chemistry and Molecular Pharmacology,
Dana-Farber Cancer Institute/Harvard Medical School
Small molecules that induce protein degradation through ligase-mediated ubiquitination, have shown considerable promise as a new pharmacological modality. Thalidomide and related IMiDs provided the clinical proof of concept, while significant
progress has recently been made towards chemically induced targeted protein degradation using heterobifunctional small molecule ligands. We will present recent work towards a better understanding of the molecular principles that govern
neo-substrate recruitment, and other small molecule degraders.
11:00 Targeting Focal Adhesion Kinase with PROTACs: From Tool to in Vivo
Robert Law, PhD, Investigator, Medicinal Chemistry, GSK Medicine Research Centre
New modalities, such as PROTACs, are powerful tools that allow biology assessment of oncogenic targets beyond the conventional kinase inhibition. Focal Adhesion Kinase (FAK) is a key mediator of tumour progression and is overexpressed
in many solid tumours; to date, inhibitors targeting FAK kinase activity have shown low success in the clinic. Here we report the design and characterization of a highly potent FAK degrader with increased efficacy over FAK inhibitor,
as well as extended
in vivo efficacy.
11:30 ADME Properties of PROTACs and Oral Bioavailability Improvement Strategies
Upendra Dahal, PhD, Senior Scientist, Pharmacokinetics and Drug Metabolism, Amgen, Inc.
PROTACs are bifunctional molecules, designed to bind with target protein and E3 ligase to degrade target protein by hijacking the cell’s own ubiquitin proteasome system. PROTACs have several advantages, but challenges remain in designing
optimal PROTACs that have acceptable absorption, distribution, metabolism, and excretion (ADME) properties to demonstrate efficacy in vivo. Literature-published PROTACs have high MW (beyond rule of
5), low permeability, and low oral bioavailability. This presentation will focus on ADME properties of PROTACs with a special focus on strategy to improve oral bioavailability.
12:00 pm Close of Conference
12:45 Dessert Break in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)
Day 1 | Day 2 | Download Brochure