Cambridge Healthtech Institute’s 10^th Annual

Kinase Inhibitor Chemistry

Emerging Targets, Tools, Opportunities and New Strategies

April 9-10, 2019

Over the past decade, kinase drug discovery has resulted in the rapid development of a new generation of anti-cancer drugs. As kinase inhibitor discovery remains an active area for a significant portion of all efforts, developers have found new ways to expand into a deeper portion of target space within the human kinome, moved beyond cancer and into chronic disease indications such as CNS disorders, as well as shifted toward allosteric modulation and harnessing slow-off or irreversible compounds. Cambridge Healthtech Institute’s 10th Annual Kinase Inhibitor Chemistry conference will once again bring together academic and industry leaders to network, collaborate and discuss advances in kinase discovery, design, screening and development.

Final Agenda

Tuesday, April 9

7:00 am Registration Open and Morning Coffee ( 20 C/D Foyer) 

PROTACs, RESEARCH UPDATES & NEXT GENERATION OF KINASES
32 A/B

8:00 Welcome Remarks

Nandini Kashyap, Conference Director, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

Erik Schaefer, President & CSO, Research & Development, AssayQuant Technologies

8:10 Development of Selective CDK Inhibitors and Degraders

Nicholas Kwiatkowski, PhD, Lead Scientist, Nathanael Gray Lab, Cancer Biology, Dana-Farber Cancer Institute

Cyclin-dependent kinases (CDKs) regulate key pathways that are frequently misregulated in cancer, making them attractive drug targets. However, the high sequence and structural conservation shared by CDK family members make the development of CDK-specific pharmacological agents difficult. We have employed several orthogonal strategies to permit the selective inhibition of distinct CDK family members and interrogation of their biological function in normal and disease states.

8:40 FEATURED PRESENTATION: Targeted Degradation of Bruton’s Tyrosine Kinase (BTK)

Matthew Calabrese, PhD, Senior Principal Scientist and Structural Biology Lab Head, Structural and Molecular Sciences, Pfizer, Inc.

Proteolysis targeting chimeras present an exciting opportunity to modulate proteins in a manner that is independent of enzymatic or signaling activity. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. We have employed a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton’s tyrosine kinase (BTK) and will share the results of this case-study and the lessons learned.

9:10 Structure-Based Predictions of CYP Selectivity, Reactivity, and Regioselectivity

Alain Ajamian, Director, Business Development, Chemical Computing Group

Cytochrome P450 oxidases (CYPs) are heme-containing enzymes responsible for clearing drug molecules through oxidative metabolism. Understanding the interactions between drug molecules and CYPs is critical for evaluating drug efficacy, clearance, toxicity, and drug-drug interactions. Although dozens of crystal structures of the five predominant CYP isoforms have been solved, most of the modeling tools that predict drug-CYP interactions completely neglect this structural information. In this work, both 2D methods and 3D methods are used to predict the isoform selectivity, small molecule reactivity, and regioselectivity of CYPs.

9:40 Networking Coffee Break

10:05 Large Scale Proteomics Approaches to Accelerate Degrader Development for Kinases and Other Challenging Targets in Cancer

Eric S. Fischer, PhD, Assistant Professor, Cancer Biology/Biological Chemistry and Molecular Pharmacology, Dana-Farber Cancer Institute/Harvard Medical School

This presentation will discuss the use of large scale chemical-proteomics approaches to accelerate the development of small molecule degraders as chemical probes and lead candidates. Small molecules capable of inducing protein degradation through recruitment of ubiquitin E3 ligases to target proteins, often referred to as degraders or PROTACs, are a new and promising drug modality. We will discuss general approaches to significantly accelerate the development of novel chemical probes for kinases and other targets in cancer.

ARTIFICIAL INTELLIGENCE IN KINASE INHIBITOR DISCOVERY

10:35 Artificial Intelligence in Kinase Inhibitor Discovery

Istvan J. Enyedy, PhD, Principal Scientist, Biogen

Machine learning in combination with automated inhibitor optimization and statistical analysis may be used to accelerate kinase inhibitor discovery. The performance of a prototype artificial intelligence protocol will be presented.

11:05 Defining the Protein Kinase Conformational Space with Machine Learning

Avner Schlessinger, PhD, Assistant Professor, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai

We have developed a machine-learning algorithm to classify kinase conformations based on structural features of the kinase domain. Our classification scheme captures known kinase conformations and defines an additional conformational state. Next, we present KinaMetrix, a comprehensive publicly accessible web-resource for studying kinase pharmacology and drug discovery. KinaMetrix enables researchers to investigate and visualize the kinase conformational space as well as small molecule substructures that exhibit conformational specificity.

11:35 Luncheon Presentation: Sensors for Continuous Monitoring of Protein Kinase & Phosphatase Activity

Erik Schaefer, President & CSO, Research & Development,  AssayQuant Technologies

AssayQuant® is combining 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.

12:20 pm Session Break

NEW TARGETS & PROMISING CANDIDATES

1:15 Chairperson’s Remarks

Lenka Munoz, PhD, Associate Professor, School of Medical Sciences, Discipline of Pathology, The University of Sydney

1:20 Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor

Tim Baffi, Graduate Student, Alexandra Newton's Lab, Department of Pharmacology, University of California San Diego

Protein kinase C (PKC) has historically been considered an oncoprotein. However, our analysis of >100 somatic mutations identified in human cancers reveals that most mutations are loss-of-function and none are activating; in contrast, germline mutations that enhance activity are associated with degenerative diseases. Our results reveal that therapeutic strategies should focus on restoring, rather than inhibiting, PKC activity in cancer.

1:50 Discovery of Soft panJAK Inhibitors for Topical Treatment of Inflammatory Skin Diseases

Daniel R. Greve, PhD, Senior Manager, Head of MedChem II, LEO Pharma A/S

The presentation covers our efforts aiming for selective, pan-JAK inhibitor molecules having a pharmacokinetic profile that allows for high local exposure combined with low systemic exposure, driven by high hepatic clearance. The lead compounds are efficacious in our mouse xenograft model of plaque psoriasis, while having promising profile in safety/ tox studies.

2:20 Targeting the Nuclear Translocation of MAPKs as a Novel Anti-Inflammatory and Anti-Cancer Therapy

Galia Maik-Rachline, PhD, Associate Staff Scientist, Biological Regulation, The Weizmann Institute of Science

We have identified two novel, distinct, regulated nuclear translocation mechanisms for ERK1/2 and JNK/p38, of which we made use of as a promising therapeutic approach. We developed a myristoylated, NTS-derived phosphomimetic peptide (EPE peptide), which blocked ERK1/2 nuclear translocation by inhibiting its interaction with importin7 (Imp7). We also developed additional p38-derived myristoylated peptide, termed PERY peptide that prevented JNK1/2 and p38α/β nuclear translocation by interfering with their binding to either Imp7 or Imp9. Our results in several cancer and inflammatory models support the use of nuclear translocation of MAPKs as a novel drug target for signaling related diseases.

2:50 Non-Kinase Targets of Protein Kinase Inhibitors

Lenka Munoz, PhD, Associate Professor, School of Medical Sciences, Discipline of Pathology, The University of Sydney

Non-kinase targets of kinase inhibitors can contribute to desired activity, side effects or act as silent bystanders. As the correct understanding of drug’s mechanism of action is critical for the interpretation and success of preclinical as well as clinical drug development, these discoveries highlight the importance of expanding the pharmacology of kinase inhibitors beyond the kinome. I will present kinase inhibitors for which other than kinase targets have been identified and discuss molecular pharmacology guidelines when using kinase inhibitors.

3:20 NEW: Selected Poster Presentation: Computational Evaluation of Potential Inhibitors for Protein Kinase CK2

Doga Ozsen, Graduate Student, Department of Chemical Engineering, Yeditepe University, Turkey

In this study, the goal is to find potential inhibitors for the serine/threonine protein kinase, CK2 (casein kinase 2) enzyme that has been associated with cancer. To do so, a variety of Thienobenzocarbazole derivatives as CK2 inhibitors were evaluated to provide an insight that will guide the new target identification and synthesis studies for the development of new derivatives with higher biological activity. The evaluation of the study was based on the only potential inhibitor that has passed to clinical phase II studies. 

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute

4:35 Plenary Technology Spotlight: Molecular Modelling for the Masses: Orion

Paul Hawkins, Head, Scientific Solutions, OpenEye Scientific

The advent of cloud computing has been transformative for many fields that utilize computation, including drug discovery. The cloud offers robust, elastic, and scalable compute resources through a browser, decreased IT overhead, costs, and time to obtain actionable results. In this presentation I illustrate how the cloud, and in particular OpenEye’s web-based platform Orion, is democratizing molecular modelling by providing easy to use access to cutting-edge molecular design tools coupled with essentially unlimited compute resources.

5:05 Plenary Keynote Introduction

Vicky Steadman, PhD, Business Line Leader, Integrated Drug Discovery, Eurofins Discovery (formerly Eurofins Pharma Discovery Services)

5:10 Plenary Keynote: Chemical Biology of Proteostasis

Jack Taunton, PhD, Professor, Department of Cellular and Molecular Pharmacology, University of California San Francisco

We have recently discovered several macrocyclic compounds that potently and selectively modulate protein homeostasis. I will discuss our recent efforts to unravel their molecular mechanisms.

6:00 Welcome Reception in the Exhibit Hall with Poster Viewing

7:00 Close of Day

Wednesday, April 10

7:30 am Continental Breakfast Breakout Discussions - View All Breakouts

ALLOSTERIC MODULATORS, KINETICS, TARGET OPTIMIZATION FOR KINASES AND PHOSPHATASES

8:30 Chairperson’s Remarks

Alexis Denis, Head of Discovery Division, Oncodesign

8:35 Make it Cyclic: A Paradigm for the Discovery of Selective Kinases Inhibitors “Nanocyclix”

Alexis Denis, Head of Discovery Division, Oncodesign

Cyclization in drug discovery is a growing paradigm. We have developed an Integrated Drug Discovery platform Nanocyclix to synthesize small libraries of macrocycles and design specific molecules through SBDD to identify new kinases inhibitor. Nanocyclix molecule are in the drug-like space and display nM potencies and good selectivity across the kinome.  Nanocyclix paradigm will be exemplified at the level of H2L and beyond in Oncology and Immuno-inflammation to illustrate the potential of the cyclization approach.

9:05 FEATURED PRESENTATION: Exploring the Hidden World of Non-Canonical Protein Phosphorylations

Tony Hunter, PhD, American Cancer Society Professor, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies

Phosphorylation of histidine, lysine and arginine, the so-called “hidden phosphoproteome”, is poorly characterized. To address this void, we developed monoclonal antibodies (mAbs) that selectively recognize the 1- and 3-isoforms of phosphohistidine (pHis) in proteins in a sequence-independent manner. We have used these mAbs in proteomic studies to identify pHis-containing proteins in cancer cell lines, and developed new protocols for enriching pHis-containing tryptic peptides and identifying sites of His phosphorylation. We have also used these mAbs for immunoblotting and immunostaining to detect and localize pHis proteins in normal and tumor tissues. Studies with these mAbs have allowed us to define a role for elevated His phosphorylation in liver cancer.

9:35 Coffee Break in the Exhibit Hall with Poster Awards Announced

Poster Awards Sponsored by Domainex

10:30 Using Fragment-Based Lead Discovery (FBLD) for Kinase Inhibitor Development

Marc O’Reilly, PhD, Senior Director of Molecular Sciences, Astex Pharmaceuticals

In this talk, I will provide examples of how Astex is exploiting high throughput protein crystallography and fragment-based lead discovery (FBLD) for kinase inhibitor development.

10:50 Selected Poster Presentation: Target Identification Using Theoretical Active Site Models

Belkıs Akbulut, Graduate Student, Department of Chemical Engineering, Yeditepe University, Turkey

We present a new computational approach to identify the multi-targeting activities of drug molecules. The strategy involves three-dimensional virtual screening of protein databases against theoretical active site models generated around drug molecules. In this work, alternative potential targets of CX-4945, a known protein kinase CK2 inhibitor, and of a Morita-Baylis-Hillman adduct, which showed biological activity on cervix cancer cells were investigated. 

11:10 Novel Design Paradigms for Protein Kinases and Phosphatases – Binding Kinetics and Allosteric Mechanisms

Gerhard Mueller, PhD, CSO, Gotham Therapeutics

We will demonstrate that a thorough understanding of the precise pharmacophoric requirements on the target’s binding site is essential to pre-engineer the desired slow off-rates into new, thus literature-unprecedented scaffolds that qualify as privileged structures for the target family of kinases.

11:30 Recent Experiences with Fragments for Kinases

Roderick Hubbard, DPhil, Professor and Senior Fellow, University of York and Vernalis

Fragments provide valuable tools for probing kinase biology and starting points for lead molecules.  I will discuss results from three recently disclosed kinase collaborative projects: DYRK1A, PAK1, LRRK2.  For DYRK1A, potent, in vivo active, selective inhibitors probed target biology; for PAK1, design of protein constructs allowed rapid progress to be made in identifying selective leads; for LRRK2 surrogate kinase enabled structure-based design of highly selective, potent, brain penetrant inhibitors.

12:00 pm Close of Conference