Kinase Inhibitor Chemistry

 

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

Wednesday, April 22

12:30 pm Registration

TRENDS IN KINASE INHIBITOR DISCOVERY AND DEVELOPMENT

1:30 Chairperson’s Remarks

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

1:40 CASE STUDY in Covalent Inhibitor Development: Discovery of a Potent Covalent Mutant-Selective EGFR Inhibitor – The Journey from High Throughput Screening to EGF816

Gerald Lelais, Ph.D., Senior Research Investigator, Medicinal Chemistry, The Genomics Institute of the Novartis Research Foundation (GNF)

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. During this case study in covalent inhibitor discovery and development we discuss our medicinal chemistry and optimization approaches employed to transform a reversible high throughput screening hit into our clinical candidate EGF816, a covalent mutant-selective EGFR inhibitor that potently inhibits both activating (e.g., L858R, exon 19 deletions) and T790M resistance mutations while sparing wild type EGFR. We will also present EGF816 activity in various in vitro cell lines and animal models representative of the relevant EGFR clinical settings, including an exon 20 insertion patient-derived xenograft (PDX) model, and report validated clinical efficacy data from the first patient treated with EGF816.

2:10 The Discovery of LY2606368, a Potent and Selective Inhibitor of Chk1 and Chk2 and Its Use as a Treatment for Cancer

David Barda, Ph.D., Research Advisor, Discovery Chemistry Research and Technologies, Eli Lilly and Company

The role of Chk1 as a regulator of cell cycle DNA damage checkpoints has been well described. Our discovery of LY2606368 helped to uncover the additional Chk1-mediated catastrophic effects early in DNA replication resulting in double stranded DNA cleavage. Replication effects coupled with inhibition of checkpoint mechanisms delivers a dual mechanism efficacy through a single biological target. We will detail the discovery through pharmacophore modeling and structure based design as well as the preclinical results achieved with this novel agent.

2:40 New Prototypes of AGC Kinase Inhibitors

Oliver Plettenburg, Ph.D., Head, Biosensors & Chemical Probes, R&D, Sanofi-Aventis

Kinase inhibitors frequently suffer from unfavorable solubility and selectivity issues. In this presentation the development of inhibitors of rho kinase, an AGC kinase acting as a key modulator of smooth muscle contractility and involved in several vascular diseases like hypertension or diabetic nephropathy, is discussed. Optimization of the lead compound resulted in the discovery of a new series of compounds with excellent selectivity and very good solubility. The binding mode will discussed and the underlying principle will be applied to another member of the AGC kinase family, PKC beta. The results of the lead optimization of that series will also be presented, leading again to soluble and specific inhibitors with good oral bioavailability.

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

A paradigm shift has occurred over the last decade in medicinal chemistry in that more emphasis is laid on the improvement of ADME-related and off-target properties, thus avoiding mere IC50-hunting campaigns. 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. The 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 Multi-Targeting Kinase Inhibitors and Combination Strategies: More Is Better

Alison O’Mahony, Ph.D., Senior Director, Biology Research, BioSeek, a division of DiscoveRx Corporation

Combination therapies are important treatment strategies for many disease indications, including oncology, cardiovascular disease, and autoimmune and infectious diseases. New combination strategies include either the use of multiple single-target agents or the development of multi-targeted compounds with rationally designed polypharmacology. The overall goals of these strategies are to improve clinical efficacy, minimize adverse events, and/or reduce the emergence of drug resistance to maintain drug response in patients. Current compound screening approaches and regulatory reviews are based primarily on the assessment of efficacy and safety of the single/selective agents, without regard to the potential for new pharmacodynamic interactions or the optimal therapeutic dose. The BioMAP screening platform enables the interrogation of individual and combined agents in a target agnostic and clinically predictive manner using a panel of human primary cell-based disease models. The resulting phenotypic activity profile can be used to compare the mechanistic signatures of target selective compounds to that of the combination or the multi-targeting agent. These data can help make rational predictions with respect to efficacy and safety, as well as guide therapeutic dosing and indication selection.

6:30 Close of Day

6:30 Dinner Short Courses*

*Separate registration required; please see 'Short Courses' page for details

Thursday, April 23

8:00 am Morning Coffee

PLENARY KEYNOTE SESSION

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

DEVELOPING NON-ATP COMPETITIVE INHIBITORS: ALLOSTERY AND PPI

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). The structure guided discovery of ABL001 targeting the myristoyl pocket of the ABL1 kinase by integrating X-ray crystallography, NMR and molecular modeling will be discussed.

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 Fragment Screening in Multiple Dimensions Using MASS-1

David Myszka, CEO, Biosensor Tools LLC

Sierra Sensors’ MASS-1 (Molecular Affinity Screening System) is an SPR biosensor platform that can do everything we’ve come to expect from label-free systems, including characterizing protein/protein, antibody/antigen, and small molecule/target interactions. But, its unique configuration of eight parallel flow channels expands the MASS-1’s throughput and versatility. For example, we can test fragment libraries faster. Or we can test compounds against more targets at the same time to identify specific binders – you’d be surprised how many compounds bind nonspecifically to proteins once you start looking carefully. In addition, the MASS-1’s internal referencing and fast data collection rate make it possible to use dissociation kinetics to demonstrate a potential hit is a real binder. It’s like having a little time machine for drug discovery.

11:30 Dynamics-Based Allostery in Protein Kinases

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

Protein kinases represent a family of highly dynamic regulatory proteins. Their structure and physical properties can be affected by multiple factors leading to a variety of biological responses. Despite decades of extensive studies the molecular mechanism of long-distance allosteric responses in many cases remains unclear. To understand the nature of allosteric signaling in protein kinases we studied microsecond-scale molecular dynamics simulations of protein kinase A. Our approach was based on community analysis that detects groups of residues that move in cohesion and represent an autonomous dynamic object within the molecule. 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 and will provide an efficient tool for structural biologists.

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

Protein-protein interactions involved in kinase regulation and substrate recognition have significant potential in drug discovery due to their unique features and therefore allow selectivity and potency of inhibition by avoiding the catalytic site. Since these interfaces typically involve shallow clefts and more diffuse interactions, they are more challenging than the ATP binding site. 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 ATP competitive inhibitors. Blocking sub-cellular localization of PLK1 is a therefore a promising strategy for next generation inhibitory compounds that avoid inhibition of other PLK family members that are tumor suppressors and therefore have opposing functions to the PLK1 cancer target.

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

INHIBITORS FOR CNS DISORDERS AND CHRONIC DISEASE

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

 MACROCYCLIC INHIBITORS FOR CNS DISORDERS AND CHRONIC DISEASE

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