6th Annual

Kinase Inhibitor Chemistry

Shaping Current and Future Development of Kinase Inhibitors

April 22-23, 2015 


Over the past decade, kinase drug discovery has resulted in the rapid development of a new generation of 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, as well as shifted toward allosteric modulation, and harnessing slow-off or irreversible compounds. Cambridge Healthtech Institute’s 6th annual Kinase Inhibitor Chemistry will once again bring together academic and industry leaders to network, collaborate and discuss advances in kinase discovery. Join fellow drug discovery scientists for this day-and-a-half meeting that is in the second half of CHI's larger Drug Discovery Chemistry event.


Up-to-date discussion on late breaking strategies for novel kinase inhibitor design.

Ann A., Senior Scientist, Pfizer

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Wednesday, April 22

12:30 pm Registration


1:30 Chairperson’s Remarks

Rogier C. Buijsman, Ph.D., Head, Chemistry, Netherlands Translational Research Center B.V. (NTRC)

1:40 Drug Discovery Considerations in the Development of Covalent Inhibitors

Cynthia Shafer, Ph.D., Group Leader, Novartis Institutes for BioMedical Research

In recent years, the number of drug candidates with a covalent mechanism of action progressing through clinical trials or being approved by the FDA has increased significantly. And as interest in covalent inhibitors has increased, the technical challenges for characterizing and optimizing these inhibitors have become evident. A number of new tools have been developed to aid this process, but these have not gained wide-spread use. This presentation will highlight a number of methods and tools useful for prosecuting covalent inhibitor drug discovery programs.

2:10 Development of Covalent Kinase Inhibitors

Eric Schwartz, Ph.D., Senior Director, Chemistry, Celgene Avilomics Research

2:40 New Prototypes of AGC Kinase Inhibitors

Oliver Plettenburg, Ph.D., Head, Chemical Biology, Sanofi

3:10 Binding Studies of Type I, II and III Kinase Inhibitors against Bcr-Abl Kinase using Back-Scattering Interferometry

Scot R. Weinberger, Ph.D., Executive Vice President, Molecular Sensing Inc.

The binding affinity of Type I, II and III Bcr-Abl kinase inhibitors with wild type and four mutant Bcr-Abl kinases were measured using Back-Scattering Interferometry (BSI).  BSI successfully demonstrated facile determination of Kd for all systems, with a high degree of concordance with IC50.  These results indicate that BSI binding studies for Type I, II and III kinase inhibitors can easily be performed, allowing for confirmation of target engagement as well as direct binding assessment of kinase inhibitors against inactive Bcr-Abl kinase.

3:40 Celebratory 10th Annual Refreshment Break in the Exhibit Hall with Poster Viewing

4:20 Next-Generation Kinase Panel Screening Measuring Target Residence Time and Kinetic Selectivity

Rogier C. Buijsman, Ph.D., Head, Chemistry, Netherlands Translational Research Center B.V. (NTRC)

Selective kinase inhibitors are optimized for increased target residence time and profiled on large panels of biochemical and cell-based assays. Genotypic, phenotypic and pathway information are combined to determine the optimal compound for a particular patient responder population. This presentation will discuss an in-depth knowledge concerning the relationship between cellular and biochemical profiles of marketed kinase inhibitors as well as insight in genetic susceptibility of these inhibitors.

4:50 Novel Kinase Inhibitor Design Paradigms: The Hydrophobic Spine and the Discovery of Slowness

Gerhard Mueller, Ph.D., Senior Vice President, Medicinal Chemistry, MercaChem BV

To improve the correlation between biochemical and cellular or in vivo efficacy, it is advantageous to optimize the residence time of compound-target complexes early in the drug discovery process. In this presentation the prospective engineering of binding kinetic signatures into inhibitors that exhibit slow koff by applying “deep-pocket-directed” scaffolds is exemplified. Details of the applied “retro-design” approach for novel kinase inhibitors that disrupt the hydrophobic spine will be highlighted by a lead finding campaign that yielded novel, selective, and highly efficacious CDK-8 inhibitors.

5:20 Breakout Discussions

In this session, attendees 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. Check our website in February to see the full listing of breakout topics and moderators.

6:20 Close of Day

6:30 Dinner Short Courses*

*Separate registration required; please see page 4 for details

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Thursday, April 23

8:00 am Morning Coffee



Fragment-Based Drug Discovery: A Fifteen Year (Re-)Evolution

Harren JhotiHarren Jhoti, Ph.D., President & CEO, Astex Pharmaceuticals

Fragment-based discovery has now been successfully established as an alternative approach to HTS and has produced multiple drug candidates that are in clinical trials. Some of the appealing features of the approach include the ability to efficiently sample chemical space and to produce drug candidates that have superior physicochemical properties. In this talk I will provide a perspective on how Fragment-Based drug discovery evolved over the last 15 years and challenged conventional thinking in Drug Discovery.

9:30 Coffee Break in the Exhibit Hall with Poster Viewing


10:10 Chairperson’s Remarks

Gerhard Mueller, Ph.D., Senior Vice President, Medicinal Chemistry, MercaChem BV

10:15 CASE STUDY: Discovery of ABL001: A New Allosteric Inhibitor of BCR-ABL

Andreas Marzinzik, Ph.D., Director, Lead Generation Chemistry, Novartis Institutes for BioMedical Research

ABL001 is a potent, selective BCR-ABL inhibitor that maintains activity across most mutations, including T315I, with a distinct, allosteric mechanism of action which recently entered Phase I development for the treatment of patients with chronic myelogenous leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL).

10:45 CASE STUDY: Enzyme Activators: Targeting AMP-Activated Protein Kinase (AMPK)

Ravi G. Kurumbail, Ph.D., Research Fellow and Structural Biology Laboratory Head, Pfizer

In recent years, AMPK has emerged as a desirable target for modulation of numerous diseases, yet clinical therapies remain elusive. We provide the full-length structure of the widely expressed α1β1γ1 isoform of mammalian AMPK, along with detailed kinetic and biophysical characterization. We characterize binding of the broadly studied synthetic activator A769662 and its analogs. Our studies follow on the heels of the recent disclosure of the α2β1γ1 structure and provide insight into the distinct molecular mechanisms of AMPK regulation by AMP and A769662.

11:15 Sponsored Presentation (Opportunity Available)

11:30 Dynamics-Based Allostery in Protein Kinases

Alexandr P. Kornev, Ph.D., Project Scientist, Department of Pharmacology, University of California, San Diego

To understand the nature of allosteric signaling in protein kinases we studied microsecond-scale molecular dynamics simulations of protein kinase A. The observed community maps were sensitive to the presence of different ligands and provide a new framework for interpreting long-distance allosteric signaling. Communication between different communities was also in agreement with the previously defined architecture of the protein kinase core based on the “hydrophobic spine” network. This allows us to suggest that community analysis can be used for other protein kinases.

12:00 pm Non-ATP Competitive Inhibitors are Selective for PLK1 and Target Tumors Resistant to Catalytic Site Compounds

Campbell McInnes, Ph.D., Associate Professor, Drug Discovery and Biomedical Sciences, University of South Carolina

We have developed and validated REPLACE as a general strategy for protein-protein interactions in the development of non-ATP competitive inhibitors of protein kinase oncology targets including in the first instance, cyclin dependent kinases through the substrate recruitment site. REPLACE has been extensively validated through application to the Polo-Box domain of PLK1 to generate selective compounds that are potent in cell culture cancer models, have cellular phenotypes consistent with inhibition and which are active against a mutant form of the kinase resistant to clinically used inhibitors.

12:30 Walk and Talk Luncheon in the Exhibit Hall with Poster Viewing (last chance for viewing)


1:40 Chairperson’s Remarks

Jan Hoflack, Ph.D., CSO, Oncodesign Biotechnology

1:45 Structure- and Property-Based Design and in vivo Profiling of Potent and Selective Tetrahydroindazole ITK Inhibitors

Zhonghua Pei, Ph.D., Senior Scientist and Project Team Leader, Discovery Chemistry, Genentech

Inhibitors of interleukin-2 inducible T cell kinase (ITK) in T cell signaling, has been pursued as a potential treatment for immune diseases such as allergic asthma. Through scaffold-hopping of the original high-throughput screen (HTS) hits of indazoles, we discovered tetrahydroindazoles (THIs) as an advanced lead series. Using structure- and property-based design, we were able to optimize multiple properties of THIs simultaneously: potency, kinase selectivity, solubility and cytotoxicity. The optimized inhibitors demonstrate excellent in vitro cellular potency and in vivo PD marker modulation.

2:15 Discovery of Substituted Aminopyridine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12)

Snahel Patel, Scientific Manager, Discovery Chemistry, Genentech, Inc.

Neurodegenerative diseases such as Alzheimer’s and Parkinson’s represent significant unmet medical needs with no therapies able to slow the course of disease. Dual Leucine Zipper Kinase (DLK) is a neuronal specific upstream regulator of the JNK pathway that was recently identified as a central regulator of degeneration in multiple contexts. Starting from a high-throughput screening hit, we have developed potent, selective and brain penetrant DLK specific inhibitors that display activity in neurodegeneration models.

2:45 Refreshment Break

3:00 Nanocyclix Approach towards Unexplored Kinases: Identification of RIP2 and SIK2 Inhibitors for Application in Auto-Immune and CNS Disorders

Jan Hoflack, Ph.D., CSO, Oncodesign Biotechnology

Oncodesign’s chemical biology approach using its macrocyclic chemistry platform has allowed the identification of potent and selective inhibitors for RIP2 and SIK2 kinases. The molecules have been used as chemical probes to validate the potential of these novel targets. Data will be presented that demonstrate the potential role of RIP2 as a target of interest in auto-immune diseases and for SIK2 in neuroprotection/ageing. The discovery and optimization of the inhibitors will be presented.

3:30 PF-06463922, a Novel Small Molecule Inhibitor of ALK/ROS1 with Preclinical Brain Availability and Broad Spectrum Potency against ALK-Resistant Mutations

Ted W. Johnson, Ph.D., Research Fellow, Medicinal Chemistry, Pfizer Oncology

PF-06463922, a novel macrocyclic inhibitor of ALK/ROS1, demonstrated low nanomolar inhibitory activity against a panel of ALK kinase domain mutants representing all of the patient crizotinib resistant mutations reported to date. Successful optimization of molecular weight and lipophilic efficiency leveraging structure-based drug design techniques led to ligands with overlapping broad spectrum potency, low transporter efflux, and brain penetration. PF-06463922 is currently in Phase 1/2 clinical trials.

4:00 Discovery of SB1578 - A JAK2 Small Molecule Macrocycle for Autoimmune Diseases

Anthony D. William, Ph.D., Senior Scientist, The Agency for Science, Technology and Research (A*STAR)-ICES

SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also demonstrates potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. Herein the design and optimization of the macrocyclic Jak2/Flt3 inhibitor will be discussed including the biochemical and cellular activities of SB1578 that translate into its high efficacy in rodent models of arthritis.

4:30 Close of Conference

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