2013 Archived Content

Fourth Annual

Kinase Inhibitor Chemistry

Charting the Chemical Space

April 17-18, 2013

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7:45 am Breakfast Workshop Presentation (Sponsorship Opportunity Available) or Morning Coffee

Exploring the Chemical Space 

8:15 Chairperson’s Opening Remarks

David Chantry, Ph.D., Senior Director, Translational and Cellular Biology, Array BioPharma


The Catalytic Domain of NF-kB Inducing Kinase Adopts an Active Conformation in the Absence of Phosphorylation

Sarah G. Hymowitz, Ph.D., Director, Department of Structural Biology, Genentech, Inc.

To better understand molecular basis of NF-kB inducing kinase (NIK) activity, we undertook a systematic expression and cloning effort to produce soluble and crystallizable NIK protein. This effort yielded crystal structures of apo human and murine NIK kinase domain as well as several structures of NIK bound to ATP-competitive inhibitors. These structures reveal the NIK kinase domain has an active-like conformation in the absence of phosphorylation and displays significant conformational variability.

9:00 Kinase Selectivity with Type 1 Inhibitors? Yes, we can!

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

Oncodesign's Nanocyclix platform of small macrocyclic kinase inhibitors allows to achieve high levels of selectivity across the kinome, without the need for reaching out to specificity pockets or targeting specific amino acids. The origin of this selectivity will be discussed using a number of experimental X-ray complexes. We will also detail the potential of these compound classes for rapid optimization based on highly consistent SAR, and discuss new data on unexplored kinases of high therapeutic interest.

9:30 Suitable Affinity Reagents for PAKs: Tight and Specific Binders from Rational Approaches

Ramesh Jha, Ph.D., Scientist, Bioscience Division, B10, MS M888, Los Alamos National Laboratory

PAKs are full of ‘hotspot’ regions for protein-protein interactions and play roles in several pathological conditions. This provides opportunities for design of affinity reagents and blockers. Using existing 3D structures of PAK1, specific binders that could distinguish ‘open’ and ‘closed ‘ states were designed. The rational approaches used to design these affinityreagents will be discussed. Finally insights will be offered for targeting the regions on PAKs with unknown structure.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

10:45 In silico Fragment-Based Discovery of Novel Classes of Potent and Selective Tyrosine Kinase Inhibitors

Hongtao Zhao, Ph.D., Scientist, Biochemistry, University of Zurich

We have developed an efficient in silico procedure called ALTA, which stays for anchor-based library tailoring approach, to interrogate a library of compounds for high throughput screening. First, small and mainly rigid virtual fragments are docked in the binding site. The fragments with most favorable calculated binding free energy (anchors) are used to identify the compounds with 2D structure containing one of these anchors, which are then submitted to flexible ligand docking. The essential of this ALTA approach is the novel fragmentation algorithm, which can generate fragments with high chemical richness that can serve as a starting point either directly for hit optimization or for identification of their “parent” compounds. This approach has led to identification of two novel classes of tyrosine kinase inhibitors, and the straightforward hit-to-lead optimization by addition of just one or two heavy atoms leads to two series of potent and selective inhibitors. The predicted binding modes were further confirmed by X-ray crystallography.

11:15 Discovery of AS1940477, a Highly Potent p38 MAPK Inhibitor

Toru Asano, Ph.D., Scientist, Drug Discovery Research, Astellas Pharma, Inc.

p38 mitogen-activated protein kinase (MAPK) plays a key role in immune responses through the production of cytokines such as TNF-alpha and IL-6. p38 MAPK is an attractive target for drugs to treat autoimmune diseases, although development of many p38 MAPK inhibitors have discontinued due to low efficacy and the need for high dosing. We have identified AS1940477 a highly potent p38 MAPK inhibitor with a novel tetrahydropyrazolopyrimidine structure. Data will be presented on the discovery and optimization of tetrahydropyrazolo-pyrimidine derivatives, including a favorable PK profile, and animal studies.

11:45 Kinase-Directed Phenotypic Screening: Identification of a Novel Target for Inflammatory Disease

David Chantry, Ph.D., Senior Director, Translational and Cellular Biology, Array BioPharma

Phenotypic screening is recognized as a powerful tool for drug discovery, but identification of molecular targets has proven challenging.  We have established a phenotypic screening platform that allows for rapid identification and validation of novel kinase targets.  We have assembled a collection of over 8 thousand compounds that cover >90% of the kinome. Using this platform we have identified a novel kinase target that regulates cytokine production by cells of the innate and adaptive immune system. Inhibitors of this kinase show anti-inflammatory activity in vitro and in vivo.

12:15 Sponsored Presentation (Opportunity Available)

12:30 Walk and Talk Luncheon in the Exhibit Hall (Last Chance for Poster and Exhibit Viewing)

Case Studies 

1:55 Chairperson’s Remarks

Tom Smithgall, Ph.D., William S. McEllroy Professor of Biochemistry; Chairman, Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine

2:00 Discovery of a Novel and Highly Selective Series of JNK Inhibitors

Leyi Gong, Ph.D., Scientist, SRI International

A novel series of highly selective JNK inhibitors based on the 4-quinolone scaffold was designed and synthesized. Structure based drug design was utilized to guide the compound design as well as improvements in the physicochemical properties of the series. One of the lead compounds exhibits an IC50 of 62/170 nM for JNK1/2, excellent kinase selectivity and impressive efficacy in a rodent asthma model.

2:30 Small Molecule Inhibitors of the c-Fes Tyrosine Kinase: Potential Applications in Myeloid Leukemia and Myeloma

Tom Smithgall, Ph.D., William S. McEllroy Professor of Biochemistry; Chairman, Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine

c-Fes is a cytoplasmic protein-tyrosine kinase that regulates normal cellular differentiation, the innate immune response, and vasculogenesis. Elevated c-Fes kinase activity is associated with Flt3+ AML and multiple myeloma. This talk will address the discovery and characterization of several classes of potent c-Fes inhibitors as well as their activity against these forms of cancer.

3:00 Chemistry to Unlock ROCK in Clinic

Olivier Defert, Ph.D., Amakem NV

Two case studies will be discussed in this lecture. First, we will focus on the design and the evaluation of a locally acting ROCK inhibitor as drug candidate for the treatment of glaucoma, AMA0076, which is currently in Phase 2 clinical development. Finally, the profile of the preclinical candidate for the treatment of respiratory diseases, AMA0247, will be shown. This compound showed efficacy in a variety of relevant in vivo models for asthma and COPD, with at least 500-fold lower exposure in the blood versus the lung tissues.

3:30 Selected Poster Presentation: Structure of the BRAF:MEK Complex Reveals Importance of Inhibitor Induced Protein Conformations for Downstream Signaling

Jawahar Sudhamsu, Ph.D., Postdoctoral Research Fellow, Structural Biology, Genentech Inc.

To understand the molecular basis of the RAF:MEK interaction, we solved the crystal structure of the BRAF:MEK1 complex. Our studies reveal the structural basis of diverse mechanisms of aberrant pathway activation by oncogenic variants of BRAF. In addition, this work also shows that inhibitor induced protein conformations can have unexpected consequences for downstream signaling.

4:00 End of Conference

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