Cambridge Healthtech Institute’s 11th Annual

Kinase Inhibitor Chemistry
( 激酶抑制剂的化学 )

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


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, RNAs as 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.

Final Agenda


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 TurisoFelix 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 CanaudGuillaume 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 effects.

9:10 Interfering with the Immune System: DMXD-011, a Potential Treatment for Systemic Lupus Erythematosus (SLE)

Perrior TrevorTrevor 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 WellsCarrow Wells, Research Associate, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill

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 ParuaPabitra 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 MirzadeganTara 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 to be AnnouncedAssayQuantTechnologies


12:30 pm 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 EnyedyIstvan 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 Sponsored Presentation (Opportunity Available)

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_MattMatt 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)


Young_WendyMedicinal 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


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 ChamberlainPhilip Chamberlain, DPhil, Executive Director, Structural and Chemical Biology, Celgene

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 ButtTauseef 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 FischerEric 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 DahalUpendra 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)

* 活动内容有可能不事先告知作更动及调整。

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