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Day 1 | Day 2 | Day 3 

Tuesday, June 18

7:45 am Breakfast Breakout Discussions

These are moderated discussions with brainstorming and interactive problem solving, allowing conference participants from diverse backgrounds to exchange ideas, experiences, and develop future collaborations around a focused topic.

Table 1: Multi-Parameter Drug Optimization – Is It Working?

• Is data quality good enough?
• How many compounds should be made and in what stage?
• What is the ideal path for optimization and how do you find it efficiently?
• What role does informatics have – small companies vs large
Moderator: Mark Ashwell, Ph.D., Vice President, Chemistry, ArQule 

Table 2: How Can We Leverage Existing Data on Protein Kinases for Inhibitor Design?
• Challenges in protein kinase data mining
• Resources needed to address data mining challenges
Moderator: Natarajan Kannan, Ph.D., Assistant Professor, Biochemistry and Molecular Biology; Institute of Bioinformatics, University of Georgia

Table 3. Next-Gen Kinase Inhibitors for Existing Kinase Treatment Options
• How to use cellular models for early detection of resistance mechanisms
• Early biomarkers for resistance mechanisms
• How to use preclinical models for next-gen kinase inhibitors
Moderator: Guido Zaman, Ph.D., Founder, Head, Biology, Netherlands Translational Research Center B.V.

8:55 Chairperson’s Remarks

Mark Ashwell, Ph.D., Vice President, Chemistry, ArQule


Property-Based Design 

9:00 Focusing on the Ligand-Protein Relationship in Activation-State Dependent Conformational Changes of Protein Kinases

Mark Ashwell, Ph.D., Vice President, Chemistry, ArQule

The traditional protein kinase inhibitor design process is being expanded as we learn more about the changing nature of the ATP-binding cleft and its switching between active and inactive states. The presentation will describe the utilization of a new understanding of the role of hydrophobic residues within the cleft and how the ligand-protein interactions influence conformational changes, providing new inhibitor design opportunities.

Promega BLACK9:30 ADP Detection Platform for Kinase Inhibitor Screening and Profiling

Hicham Zegzouti, Ph.D., Senior Research Scientist, R&D, Promega Corporation

The ADP-Glo™ kinase assay is a universal and robust assay for determining kinase activity using the universal kinase reaction product ADP as readout. Because of its high sensitivity, we utilized this format to profile 174 kinases covering the various families of the kinome. These enzymes were grouped in multi-well strips containing eight enzymes each, and were optimized for generating an activity within the linear response of the kinase. Here we present the profiling of several kinase inhibitors using these standardized profiling systems. The ADP-Glo™ platform offers tremendous benefits to kinase screening and profiling programs along with the ability to study the mode of action of various inhibitors in an affordable way using one assay format during the various stages of drug discovery.


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

10:45 Structure and Property Based Design of CK2 Kinase Inhibitors

James Dowling, Ph.D., Scientist, Astrazeneca

The serine/threonine protein kinase CK2 regulates cell growth, proliferation and evasion of apoptosis by phosphorylation of a range of substrates in several critical cellular signaling pathways and is an attractive target for drug discovery in oncology. To identify chemical starting points against the target, we screened a kinase-focused subset of the AZ compound collection and applied structure-based approaches to further enrich and diversify the output. Property-based design strategies were integrated to identify series with sufficient enzymatic potency, kinase selectivity and molecular characteristics that would enable us to carry out pharmacodynamic and efficacy studies using an orally administered agent. Agents derived from these approaches modulate pAKTS129, a direct substrate of CK2, in vitro and in vivo, and exhibit tumor growth inhibition when evaluated in disease model studies.

Developing Selective Inhibitors 

11:15 Evolutionary and Semantic Web Applications in Protein Kinase Inhibitor Design

Natarajan Kannan, Ph.D., Assistant Professor, Biochemistry and Molecular Biology & Institute of Bioinformatics, University of Georgia, Athens

Protein kinases display complex sequence-structure-function relationships, a detailed understanding of which is necessary for the development of selective protein kinase inhibitors.  This talk describes how evolutionary- and ontology-based analysis of protein kinase data can provide new insights into sequence-structure-function relationships, and aid in the development of selective protein kinase inhibitors.

11:45 Selective Inhibition of Kinase-Driven Pathways; Exploiting Demure Features

Ellen R. Laird, Ph.D. Research Fellow, Array BioPharma

Selective inhibition of nearly any given protein kinase continues to challenge investigators. Literature reviews generally focus upon gross differences in kinase fold, with emphasis on “inactive” vs. “active” conformations, yet many of these compounds remain stubbornly promiscuous. We have curated and analyzed a sizeable collection of X-ray crystal structures of diverse kinases, many of which are proprietary. We have identified additional sources for selectivity by consideration of nuances at the periphery of active or inactive folds. Differences in sidechain rotamer preferences and solvation, cleft dimension, features of the active site floor, the P-loop, and the C-helix often contribute to hypotheses that enable SAR interpretation and further compound design. This talk will draw upon prominent examples of inhibitors that owe their selectivity to these subtle differences, with particular emphasis on our own experiences with AKT, B-Raf, and Erb-B2.

DiscoverRx 12:15 pm Luncheon Presentation: Application of KINOMEscan® to the Classification of Inhibitor Binding Mode and Association/Dissociation Kinetics

Brian Manning, Ph.D., Senior Director, Business Development, DiscoveRx Corporation

Kinase inhibitor drug discovery requires the optimization of several drug-like properties, including potency & selectivity, cellular potency, potency against clinical mutants, pharmacokinetics and pharmacodynamics. Several of these properties are affected by an inhibitor’s binding mode and association/dissociation kinetics – two parameters that have been traditionally problematic to measure routinely during lead optimization. We will discuss scanMODE® and scanKINETIC™ - biochemical tools that classify inhibitor binding mode (Type I or Type II) and association/dissociation kinetics, respectively.

1:35 Chairperson’s Remarks

Natarajan Kannan, Ph.D., Assistant Professor, Biochemistry and Molecular Biology; Institute of Bioinformatics, University of Georgia

1:40 Structure-Based Design of Selective hSmg-1 Kinase Inhibitors

Eric Bennett, Ph.D., Principal Scientist, Computational Protein Engineering, Pfizer

hSmg-1 kinase plays a key role in cellular genotoxic stress response and contributes to tumor growth and resistance to chemotherapy. To understand the functional role of inhibiting this underexplored Ser-Thr kinase, we identified pyrimidine-based, highly hSmg-1 selective kinase inhibitors. Use of structure based optimization to achieve selectivity will be discussed in detail.

2:10 Drug Screening on Signal Transduction Proteins via µ-Patterned Surfaces

Julian Weghuber, Ph.D., Principal Investigator, School of Engineering and Environmental Sciences, University of Applied Sciences, Upper Austria

Membrane-localized protein receptors activated by various messengers (including receptor tyrosine kinases) and their cytosolic binding partners are key to transmit important signals into the cell. To analyze such receptor-effector protein interactions we use micro-structured surfaces in combination with fluorescent (TIRF) microscopy. This technique is capable of detecting and also quantifying protein-protein interactions in a live-cell context (Schwarzenbacher et al., 2008; Nature Methods). Here we present new insights into the EGF-receptor – Grb2 interaction and describe the usefulness of our method in order to search for or better characterize new drugs affecting EGFR-based signaling.

2:40 The SYK–BTK Axis as a Drug Target for Autoimmune Disorders

Cheng Liao, Ph.D., Senior Scientist II, EMD Serono Research & Development Institute

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.

3:10 Refreshment Break in the Exhibit Hall with Poster Viewing

Case Studies 

4:00 Discovery and Development of Novel, Isoform-Selective PI3K Inhibitors for the Treatment of Immune-Inflammatory Diseases and Cancer

Stephen J. Shuttleworth, Ph.D., FRSC CChem, CSO, Karus Therapeutics Ltd.

Our R&D programs at Karus are centered on the design and development of subtype-selective small molecule inhibitors of PI3K and of HDAC. This talk will outline our approaches to PI3K isoform-specific inhibitor discovery and development for the treatment of Th17 cell-mediated immune-inflammatory diseases, and of specific tumor types.

4:30 Discovery and Development of Jakafi for Myelofibrosis

Kris Vaddi, DVM, Ph.D., Group Vice President, Pharmacology and Toxicology, Incyte Pharmaceuticals

Jakafi (ruxolitinib) is a potent, selective and first in-class JAK1 and JAK2 inhibitor, approved by USFDA for the treatment of patients with intermediate- and high-risk myelofibrosis. Myelofibrosis is a serious and life-threatening myeloproliferative neoplasm (MPN), but unlike CML is Philadelphia chromosome negative. An important discovery in late 2004 that identified a somatic gain-of-function mutation  known as JAK2 V617F in MPN patients provided first molecular and genetic evidence that linked JAK-STAT dysregulation to the pathogenesis of MPNs. Drug discovery program at Incyte  aimed at developing JAK inhibitors began in early 2003, almost 2 years ahead of the discovery of JAK2V617F with the recognition that JAK-STAT pathway is an important oncogenic and inflammatory mechanism. This early start allowed Incyte to identify Jakafi in <1 year after the identification of the mutation and gain FDA approval in 6 years.   Presentation will outline the challenges, major milestones and future opportunities that highlight the discovery and development of Jakafi.

5:00 Close of Day

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