2013 Archived Content

Fourth Annual

Kinase Inhibitor Chemistry

Charting the Chemical Space

April 17-18, 2013

What are the current challenges and bottlenecks in the field of kinase inhibitors? Is it more important to target efficiency or to optimize specificity? What is the best way to modulate inhibitors and to interfere with the binding sites? What is still new and what are novel opportunities in the chemical space of kinases?
Some of the current challenges the industry is facing are drug resistance, unwanted side effects, finding efficient screening and profiling technologies and discovering novel applications for existing inhibitors. This meeting is bringing top leaders in the field together to discuss their current work and progress in these areas.

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WEDNESDAY, APRIL 17

12:30 pm Registration


Optimizing Selectivity 

1:30 Chairperson’s Opening Remarks

Deborah J. Moshinsky, Ph.D., Founder and President, Cell Assay Innovations, LLC

1:40 Discovery of Highly Potent, Selective and Brain-Penetrable LRRK2 Inhibitors

Anthony Estrada, Ph.D., Scientist, Medicinal Chemistry, Genentech, Inc.

There is a high demand for potent, selective and brain-penetrable LRRK2 inhibitors to test whether inhibition of LRRK2 kinase activity will reduce the rate of disease progression in Parkinson’s disease patients (PD) or animal models of PD. Starting from ligand efficient aminopyrimidine LRRK2 inhibitors, a thorough lead optimization process using property and structure-based drug design was executed. High throughput in vivo pharmacokinetic profiling enabled rapid validation of in vitro permeability and metabolic stability predictions. This resulted in the rapid discovery of inhibitors possessing an ideal balance of LRRK2 cellular potency, broad kinase selectivity, metabolic stability, and brain penetration across multiple species.

2:10 Structural and Biophysical Insights into an Allosteric Syk Kinase Inhibitor

Ann Aulabaugh, Ph.D., Senior Scientist, Structural Biology and Biophysics, Pfizer

2:40 Type II Protein Kinase Inhibitors for Increased Biochemical Efficiency and Kinome Selectivity: Experiences with PYK2 and SYK

Seungil Han, Ph.D., Senior Principal Scientist, Pfizer

In our pursuit to develop highly selective protein kinase inhibitors with increased biochemical efficiency in a cellular environment, we embarked on a systematic program to identify and characterize Type II inhibitors for two protein kinases, PYK2 and SYK. Application of different structural biology techniques along with sophisticated computational approaches have led to the identification of ‘DFG-out’ or ‘C-helix-out’ inhibitors of PYK2 and SYK. Crystal structures of these kinases with Type II inhibitors reveal the inherent dynamics within the kinase module of PYK2 and SYK that result in novel druggable binding sites outside of their adenine site. I will discuss our experiences in developing selective Type II inhibitors of protein kinases.

3:10 The SYK–BTK Axis as a Drug Target for Autoimmune Disorders

Seng-Lai Tan, Ph.D., Consultant, Global Medical Affairs, F- Hoffmann-La Roche Ltd., Basel, Switzerland

Spleen Tyrosine Kinase (SYK) and Bruton's Tyrosine Kinase (BTK) are non-receptor cytoplasmic tyrosine kinases that are primarily expressed in cells of hematopoietic lineage. Both are key mediators in coupling activated immunoreceptors to downstream signaling events that affect diverse biological functions, from cellular proliferation, differentiation and adhesion to innate and adaptive immune responses. As such, pharmacological inhibitors of SYK or BTK are being actively pursued as potential immunomodulatory agents for the treatment of autoimmune and inflammatory disorders. Here, we review and discuss recent insights into the emerging role of the SYK–BTK axis in innate immune cell functions, and our experience in developing selective SYK and BTK inhibitors.

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

4:20 Cell-Based Kinase Assays in Drug Discovery: Application to Selectivity Analysis and Personalized Medicine

Deborah J. Moshinsky, Ph.D., Founder and President, Cell Assay Innovations, LLC

This talk will focus on specific cellular model systems utilized in kinase drug discovery for potency, selectivity, and mechanism of action analyses.  Examples of how these cell-based systems enable more physiologically relevant selectivity assessments will be given.  Additionally, application of cellular kinase assays to personalized medicine will be outlined, with a particular emphasis on screening for inhibitors of drug-resistant mutant kinases.

4:50 Tricyclic Kinase Inhibitors

Kristine E. Frank, Ph.D., Senior Scientist III, Hit to Lead Chemistry, Abbvie

To date, ATP-mimetic kinase inhibitors have focused primarily on monocyclic and bicyclic heterocyclic cores. We sought to expand on the repertoire of potential cores for kinase inhibition by exploring tricyclic variants of classical bicyclic hinge binding motifs such as pyrrolopyridine and pyrrolopyrazine.  A diverse collection of tricycles were prepared to investigate the electronics of each system and their ability to act as kinase hinge binders with differential selectivity.  These structures have good calculated physicochemical properties and may have general use as scaffolds for kinase inhibitor projects.

5:20 Moderated Breakout Discussions

In this interactive session, several topics will be offered for discussions and delegates are invited to choose a topic of interest and join the moderated discussion at hand. In this informal setting, participants are encouraged to share examples from their work, vet ideas with peers and be part of a group problem-solving endeavor. We emphasize that this is an informal exchange amongst scientists and is not meant to be, in any way, a product promoting session.

TABLE ONE: Best Practices in Discovery and Design of Kinase Inhibitors: HTS, Fragment-based, Modeling, Conformation, Allostery, Kinetics

Moderator: Terry Richard Stouch, Ph.D., President, Science For Solutions, LLC


• Selectivity: How much is enough? how much is too much?
• Optimizing kinetics
• Value of modeling - value of dynamics
• Value and use of fragment based design
• where is crystallography a help and where is it a hinderance
• surprises in kinase conformation
• Is protein modeling and simulation a good starting point in inhibitor design
• Best use and value of kinase screening panels
• Value of high-throughput
• Kinase inhibitor chemotypes, is it being saturated?
• Finding and exploiting allosteric sites
• Kinase assays: what works best

TABLE TWO: PKPD for Chemists

Moderator: Jan Wahlstrom, Ph.D., Principal Scientist, Amgen

• What are the fundamentals of PKPD?
• Where can PKPD be applied to add value?
• How can PKPD be integrated into the drug discovery/development paradigm?
• What are common misperceptions involving PKPD


TABLE THREE: The return of kinase inhibitors as anti-inflammatories: Lessons learned and path forward

Moderator: Seng-Lai Tan, Ph.D., Consultant, F. Hoffmann-La Roche


• Why have JAK inhibitors seen clinical success while others have failed?
• What are the major challenges in kinase inhibitor discovery for anti-inflammatories?
• The new kids on the block: SYK, BTK and PI3K
• What are the other emerging pathways and kinases?
• Will oral kinase inhibitors offer superior efficacy over biologics?
• What are the best practices for target identification and validation of novel kinases?
• Do covalent inhibitors have a place in anti-inflammatories?

6:20 End of Day

6:30 - 9:00 pm Dinner Short Courses (Separate registration required)



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