5th Annual

Kinase Inhibitor Chemistry

Expanding the Druggable Kinome

April 24-25, 2014 

 
 

The human kinome has proven to be a large class of chemically tractable drug targets, with a significant portion of drug development efforts geared toward the discovery and optimization of chemical matter modulating kinase activity. Yet, despite the hundreds of kinase inhibitors currently in discovery, preclinical and clinical phases, a relatively small subset of the kinome has been thoroughly explored with selective small molecule inhibitors. Thus, in this highly competitive space, continued success requires the identification of novel kinase targets, obtaining target selectivity and specificity, developing compounds with non-traditional mechanisms of inhibition - such as binding outside the ATP site or cyclic inhibitors - and applying kinase inhibitors to non-oncology indications. Cambridge Healthtech Institute’s fifth annual Kinase Inhibitor Chemistry will once again join academic and industry leaders to network, collaborate and discuss practical solutions to these challenges, while exploring the ever expanding arena of kinase drug discovery.

 

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

Ann A., Senior Scientist, Pfizer
 

 

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Thursday, April 24 - Day 1 

 
 

12:30 pm Registration

 

OPTIMIZING NEXT-GENERATION KINASE INHIBITORS 

1:30 Chairperson’s Opening Remarks

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

1:40 Combining Cellular and Biochemical Panel Profiling for the Development of Selective Kinase Inhibitors

Rogier BuijsmanRogier 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.

2:10 Binding Kinetics as Optimization Parameter for Kinase and Epigenetic Enzyme Inhibitors:
The Discovery of Slowness

Gerhard MuellerGerhard 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 consider the lifetime of the ligand-target complex by determining and optimizing the residence time of compound-target complexes. In this presentation the relevance of binding kinetic attributes of inhibitors against kinases, as well as a variety of epigenetic targets, such as histone-deacetylases (HDACs) and histone-lysinemethyl-transferases (HKMTs) is emphasized. In the area of protein kinases, the prospective engineering of a binding kinetic signature into inhibitors that exhibit a slow koff by applying “deep-pocket-directed” scaffolds is exemplified on the light of highly selective CDK8 inhibitors with potent anti-proliferative efficacy.

2:40 The Use of Solvent Mapping for Improving Docking and Scoring

Istvan EnyedyIstvan Enyedy, Ph.D., Senior Scientist, Chemistry, Biogen Idec

Target structure-based “hit” optimization in a drug discovery project is challenging from the computational point of view. Scoring functions cannot predict binding affinity, thus computational chemists must use their intuition or prior knowledge about the target class to prioritize compounds for synthesis. As the pharmaceutical industry targets novel protein classes, computational chemists must use software to build their know-how about the new targets. The talk will focus on how we can guide docking and scoring by using solvent mapping for identifying pockets suitable for small molecules and by getting information from the binding modes of the set of 16 fragments used by ATLAS. The use of fragment clusters for defining the shape and size of the grid used for docking will be demonstrated using FRED and HYBRID docking protocols from OpenEye on nine kinases, more than 200 protein structures. The presentation will highlight the influence of the binding site conformation, size of the docking grid, and target on the outcome of docking.

 

3:10 The Discovery and Profile of Narrow Spectrum Kinase Inhibitors as Novel Treatments for Inflammatory Pulmonary Diseases

Stuart OnionsStuart Onions, Ph.D., Director, Research Management, Sygnature Discovery Ltd.

COPD affects 65 million people worldwide and by 2030 could be the third largest cause of death. Corticosteroids are the current front line therapy, but cannot prevent disease progression and new, improved therapies are required. This presentation details the discovery of narrow spectrum kinase inhibitors which directly target the lung, have optimal duration of action and reduced toxicity by minimizing systemic exposure.

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:20 Design of Type 1 and Type 2 Selective Inhibitors of Maternal Embryonic Leucine-Zipper Kinase (MELK) Using Fragment-Based Drug Discovery

Valerio BerdiniValerio Berdini, Associate Director, Computational Chemistry, Astex Pharmaceutical

Maternal embryonic leucine-zipper kinase (MELK) is a serine/threonine kinase belonging to the CAMK family. Early studies suggested that MELK might be a promising target for the treatment of several cancers. Increased MELK expression has been reported in different tumor tissues. The lack of public domain selective inhibitors has presented a challenge for understanding the physiological role of MELK in more detail. The highly selective and conformationally diverse compounds presented in this talk, have the potential to be chemical probes for elucidating the physical role of this protein. The talk will discuss how X-ray crystallographic fragment-based screening (Pyramid™) identified hits that led to potent and highly selective chemical leads. The advantages offered by the fragment-based approach coupled with high-throughput X-ray crystallography will be elucidated with two case studies showing how, both exquisitely, specific type 1 inhibitors and novel type 2 inhibitors were discovered.

4:50 Next-Generation Protein Kinase Inhibitors When Selectivity Counts

Stefan LauferStefan Laufer, Ph.D., Chairman, Pharmaceutical & Medicinal Chemistry, Pharmacy & Biochemistry, University of Tuebingen

Highly selective PKIs are valuable probes and tools in anti-cancer and anti-inflammatory drug discovery. By combining design strategies of both the traxler kinase paradigm with glycin-flip and rigid linear binding concepts, we developed a platform for kinase inhibitors with extreme selectivity. Reducing ATP-dependence was achieved by disrupting the hydrophobic spine (type 1 1/2 inhibitors). This presentation will discuss a design approach to highly selective protein kinase inhibitors (selectivity > 1000), generally suitable for 46 out of 518 kinases. Examples including p38, JAK3, c-Met, CK1delta will be shown. A case study for p38 and further perspectives will be discussed as well.

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.

Topic 7: Expanding the Druggable Kinome

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

• What are the critical limitations of developing inhibitors for unexplored kinases in and outside the field of oncology?
• What measures are being taken to overcome these issues?
• What are clear-cut and feasible opportunities?

Topic 8: Kinase Targets to Avoid Inhibiting

Moderator: Istvan Enyedy, Ph.D., Senior Scientist, Chemistry, Biogen Idec

• What potential adverse side effects still exist for "selective" kinase inhibitors?
• Which kinases do we not want to inhibit?

Topic 9: Irreversible Kinase Inhibitors

Moderator: Stefan Laufer, Ph.D., Chairman, Pharmaceutical & Medicinal Chemistry, Pharmacy & Biochemistry, University of Tuebingen

• Challenges and opportunities in irreversible inhibitors for cancer and non-cancer kinases
• Highly mutant specific inhibitors, a new avenue or a dead end?

Topic 10: Optimizing Next-Generation Kinase Inhibitors

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

• Opportunities and challenges in optimizing next generation kinase inhibitors
 -     How to identify narrow spectrum kinase inhibitors early on?
 -     Optimization on the basis of biochemical properties or cellular activity?
 -     Optimizing kinetic selectivity rather than biochemical selectivity?
• Is the golden age of kinase inhibitors already over? Or is the best yet to come?
• Do we focus too much on improving existing therapies and neglect the pool of unexplored kinases?

6:20 Close of Day

6:30 Dinner Short Courses*


Friday, April 25 - Day 2 

 
 

7:30 am Morning Coffee

 

EMERGING APPROACHES FOR INHIBITION 

8:00 Chairperson’s Remarks

 

8:05 Featured Presentation: Conformationally Constrained Diaminopyrimidines: Identification of Potent ALK Inhibitors

Bruce DorseyBruce Dorsey, Ph.D., Senior Director, Medicinal Chemistry, Teva Pharmaceuticals

Anaplastic lymphoma kinase (ALK) is a cell membrane receptor tyrosine kinase associated with chromosomal translocations resulting in the identification of oncogenic proteins that drive a subset of specific cancers. Deregulated ALK acts through over expression in human glioblastoma or chromosome translocation in both anaplastic large cell lymphoma (NPM-ALK) and non-small cell lung cancer (EML4-ALK). Interest in ALK has increased significantly with the recent FDA approval of crizotinib for the treatment of locally advanced or metastatic NSCLC that is ALK positive. Here we present the results of our efforts to design and synthesize clinically relevant ALK inhibitors.

8:35 Modulating JAK Kinase Activity and Selectivity through the Intervention of Small Molecule Macrocycles: Discovery of SB1518 (Pacritinib)

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

The most advanced small molecule macrocycle Pacritinib has shown promising activity in late phase clinical trials for the treatment of Myelofibrosis. Here, the design and optimization of macrocyclic Jak2/Flt3 inhibitors will be discussed.


9:05 Development of Highly Potent and Selective Reversible Covalent BTK Inhibitors

Erik Verner, Ph.D., Director, Chemistry, Principia Biopharma

9:35 Coffee Break in the Exhibit Hall with Poster Viewing

 

DEVELOPMENT OF NOVEL KINASE INHIBITORS 

10:20 The Discovery of Novel Selective Anaplastic Lymphoma Kinase Inhibitors

Pierre MichellysPierre-Yves Michellys, Ph.D., Director, Medicinal Chemistry, The Genomics Institute of the Novartis Research Foundation (GNF)

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g. NPM-ALK in ALCL or EML4-ALK in NSCLC) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.gneuroblastoma). Presented is the discovery of novel and selective anaplastic lymphoma kinase inhibitors that emerged from the parallel medicinal chemistry effort done on LDK378. Synthesis, structure activity relationships (SAR) pre-clinical profile and in vivo efficacy xenograft models are described as well as the rational design strategy employed.

10:50 Novel IRAK4 Inhibitors for Oncology and Inflammation

Susanta SamajdarSusanta Samajdar, Ph.D., Research Director, Medicinal Chemistry, Aurigene Discovery Technologies Limited

This presentation will discuss the discovery and optimization of hit series, some preliminary in vivo data, combination therapy strategy, present focus and further advancements.



11:20 Discovery of a Selective PI3Kβ Clinical Candidate - Rationales for Selectivity

Laurent Schio Laurent Schio, Ph.D., Director, Medicinal Chemistry, Oncology, Sanofi

Abnormal PI3K pathway activation is recurrent in many cancer types, as a result of either receptor tyrosine kinase activations or somatic mutations of major components of the pathway. Most PI3K inhibitors currently in clinical development inhibit the four class I PI3K isoforms resulting in side effects and dose limitations in patients. We will report here the discovery of selective PI3Kβ inhibitors from high throughput screening and drug design approaches. X-Ray analysis of co-structures obtained with different PI3K isoforms could not explain the level selectivity observed. Further biophysical studies and state of the art in silico calculations have allowed to establish a rationale for selectivity despite high sequence similarity in the ATP binding site of the PI3Ks.

11:50 Selected Poster Presenter

12:05 pm Walk and Talk Luncheon in the Exhibit Hall with Poster Viewing (last chance for viewing)

 

EXPANDING THE DRUGGABLE KINOME - BEYOND ONCOLOGY 

1:25 Chairperson’s Remarks

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

1:30 Selective and Brain-Permeable Polo-Like Kinase-2 (Plk-2) Inhibitors

Dean Richard Artis, Ph.D., Senior Vice President, Molecular Discovery, Elan

2:00 Nanocyclix Approach towards Unexplored Kinases: Identification of RIP2 and SIK2 Inhibitors for Application in Auto-Immune and CNS Disorders

Jan HoflackJan 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.

2:30 Identification of Potent, Selective and Orally Bioavailable TYK2 Inhibitors for Psoriasis

Jun Liang, Ph.D., Scientist, Discovery Chemistry, Genentech, Inc.

We have sought potent and selective TYK2 inhibitors, in order to inhibit the interleukin-12 (IL-12) pathway. A fragment-like hit was identified through high throughput screening of the Genentech library and it was optimized using structure-based and property-guided design. The resulting potent and selective TYK2 inhibitor blocked interferon-gamma production in vitro and in vivo, demonstrating for the first time that selective TYK2 inhibition is an effective strategy to inhibit IL-12 signaling pathway.

3:00 Novel Triazolopyridine Compounds as Selective JAK1 Inhibitors: From Target Discovery to GLPG0634

Christel MenetChristel Menet, Ph.D., Senior Therapeutic Area Lead & Project Director, Galapagos NV

We have identified a series of compounds that showed good activity in biochemical and cellular assays against the novel drug target JAK1. This series demonstrated promising ADME/PK properties and several compounds showed activity in in vivo models of RA. The lead compound, GLPG0634, is the first JAK1 selective compound that has demonstrated clinical efficacy and a favorable safety profile in two Phase IIA clinical studies in patients with rheumatoid arthritis. Discovery and SAR of the series will be presented.

3:30 Close of Conference



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