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 Stay on to attend Structure-Based Design (June 6 - 8)

Tuesday, June 5

7:30 am Morning Coffee (Breakfast Workshop Sponsorship Available)

8:30 Chairperson’s Remarks

8:35 PI3K Inhibitors As Therapeutics For Inflammatory-Based Diseases
John Doukas, Ph.D.,Senior Director, Pharmacology,TargeGen, Inc.
Genetic deletion studies have demonstrated the regulatory roles that phosphoinositide 3-kinases play in inflammatory reactions. Our efforts to develop PI3K inhibitors will be described, and in particular our advancement into the clinic of an isoform-specific PI3Kg/d inhibitor for the reduction of reperfusion injury in myocardial infarction. 

9:05 The Anti-Inflammatory Protein Tristetraprolin is Phosphorylated at Multiple Sites by Multiple Protein Kinases
Heping Cao, Ph.D., Research Biologist, Human Nutrition Research Center, USDA/ARS
Transgenic mice without tristetraprolin (TTP) protein develop a profound inflammatory syndrome with erosive arthritis, autoimmunity, and myeloid hyperplasia. TTP is a hyperphosphorylated zinc finger protein that binds to AU-rich elements within certain mRNAs such as tumor necrosis factor mRNA and causes destabilization of those mRNAs. We have identified multiple phosphorylation sites in human TTP by site-directed mutagenesis and mass spectrometry. We have also determined that TTP is phosphorylated in vivo and/or in vitro by a number of protein kinases including p42 MAP kinase, p38 MAP kinase, JNK, GSK3, MK2, PKA, PKB, and PKC.

9:35 Exploring Chemical Space in Protein Kinase Inhibitor Drug Discovery
Tomi Sawyer, Ph.D., Senior Director, Department of Chemical Sciences, Pfizer Global R&D
Significant advances in protein kinase drug discovery have been made over the last three decades. This presentation will highlight key achievements as exemplified by pioneering work focused on a few protein kinases relative to ATP-competitive and non-ATP-competitive inhibitors (e.g., Src, Abl, and MEK). This illustrates the integration of structural biology, drug design, chemistry, and signal transduction pathway biology strategies to provide molecular tools and clinical candidates for a wide range of diseases involving protein kinases.

10:05 Coffee Break, Exhibit and Poster Viewing

10:45 Privileged Structure Concept Applied to Protein Kinases: From 1st Generation Inhibitors to Chemo- Kinomics
Gerhard Mueller, Ph.D., Vice President, Drug Discovery, GPC Biotech AG
Today’s target proteins of pharmaceutical relevance cluster into multi-member gene families, thus offering medicinal chemistry a systematic approach to broadly exploit once established agonist, antagonist, or inhibitor concepts. In this context, the family of protein kinases emerged as one, if not the most prominent target class for modern drug discovery and development, convincingly proven by the recently launched kinase inhibitors. In this talk, a systematic medicinal chemistry concept, applied to the gene family of protein kinases, is presented that takes advantage of densely populated protein families, exhibiting family-wide molecular recognition characteristics. The privileged structure concept attempts to encode those structural and functional commonalities that are conserved throughout, e.g., the kinase family into small-molecule inhibitors that, upon further ornamentation, allow for generation of highly active and selective compounds suitable for lead finding and optimization campaigns. The structural commonalities that serve as negative imprint for the design of tailor-made kinase-directed privileged structures will be discussed in detail, highlighting the basic ground rules for a systematic chemo-kinomics approach.

11:15 Thienopyridine-Based Multitargeted Kinase Inhibitors
Arkadii Vaisburg, Ph.D., Director, Medicinal Chemistry, MethylGene, Inc.
We have identified a series of novel thienopyridine-based small molecule inhibitors with potent activity against the c-MET receptor and all three receptors of the VEGFR family. Molecules of these series also have significant activity against other therapeutically relevant kinases including Tie-2 and Ron. 
Profiling of these chemical entities in whole cells demonstrates potent inhibition of HGF dependent c-MET phosphorylation, c-MET dependent phenotypes such as HGF-stimulated cell scattering and migration. Importantly, these molecules also significantly suppress the growth of tumor cells in which c-MET is constitutively active. Lead molecules demonstrate potent activity in numerous in vitro angiogenesis assays e.g., VEGF-stimulated VEGFR2/KDR autophosphorylation. They also possess broad spectrum anti-tumor activity when dosed orally once daily in several human tumor xenograft models with no associated body weight loss or marrow suppressive effects.

1:40 Chairperson’s Remarks

1:45 Strategies for Cost Effective Screening and Profiling
Ulf Boemer, Ph.D., Head, Technology Development & HTS Infrastructure, Research Center Europe, AD/HTS, Schering AG
This presentation will address different strategies for biochemical and cell-based screening for kinase inhibitors. It will show how assay development, primary screening and profiling are harmonized throughout the drug discovery process at Schering to optimally exploit the kinase target family in a cost-effective manner.

2:15 Functional Interrogation of the Kinome Using Nucleotide Acyl Phosphates
Matthew Patricelli P., Director, Discovery Technology, ActivX Biosciences
The central role of protein kinases in signal transduction pathways has generated intense interest in targeting these enzymes for a wide range of therapeutic indications. Here we report a method for identifying and quantifying protein kinases in any biological sample or tissue from any species. The procedure relies on acyl phosphate- containing nucleotides, prepared from a biotin derivative and ATP or ADP. The acyl phosphate probes react selectively and covalently at the ATP binding sites of at least 75% of the known human protein kinases. Biotinylated peptide fragments from labeled proteomes are captured, and then sequenced and identified using a massspectrometry based analysis platform to determine the kinases present and their relative levels. Further, direct competition between the probes and inhibitors can be measured to determine inhibitor potency and selectivity against native protein kinases, as well as hundreds of other ATPases. The ability to broadly profile kinase activities in native proteomes offers an exciting prospect for both target discovery and inhibitor selectivity profiling.

3:15 Refreshment Break, Exhibit and Poster Viewing

4:00 Genome-Wide Identification of Kinase Targets in Human B Lymphocytes
Andrea Califano, Professor, C2B2, Columbia University
Transcriptional interactions in the cell are modulated by a variety of mechanisms that prevent their representation as static interactions between a transcription factor and its targets. These include, among others, transcription factor modification by phosphorylation and acetylation, formation of active complexes with one or more transcriptional co-factors, and protein specific degradation and stabilization processes. We introduce a method, MINDY (Modulator Inference by Network Dynamics), for the genome-wide identification of post-translational modulators of transcription factor activity. Inferred modulators, such as an activating kinase, modify the ability of a TF to activate/repress its targets, thus providing cellular context specificity. Extensive biochemical validation of the algorithm on the MYC transcriptional program in human B cells show that the algorithm is extremely effective in identifying bona fide modulators of the TF, including protein kinases, phosphatases, acetyltransferases, and co-transcription factors. A full analysis of TF modulation by kinases in human B cells provides a wide repertoire of potential new drug targets that specifically up- or down-regulate a given transcriptional program.

4:30 Identification of Potent Kinase Inhibitors Against EGFR and its Signaling Pathways Using A Label-Free Cell Based Assay
Josephine Atienza, Ph.D., Senior Scientist, Cell Biology and Assay Development, ACEA Biosciences, Inc.
We report the identification of potent small molecule inhibitors of EGFR using a novel, quantitative, real-time, and label-free cellular assay. This cellular assay allows for the identification of both competitive and allosteric type of EGFR inhibitors. Using EGF-mediated changes in morphology as a read-out, a focused kinase library of about 1254 compounds was initially screened. From this screen, a benzothiazole based compound that inhibits EGFR kinase activity was identified. In addition, a compound was also identified that inhibited EGF dependent activity but not EGFR tyrosine kinase activity. The activities of these compounds on proliferation of a panel of normal and cancer cell lines including EGFR and erbB2 overexpressing lines and on different signaling pathways activated by EGFR were also examined. An additional 10,000 compounds of a focused kinase library was screened. The unbiased nature of this screen can lead to classes of compounds that have novel mechanism of inhibition and utility against resistant forms of the kinase. Furthermore, the utility of label-free cell-based assays as a screening tool will also be discussed.

5:45 End of Day Two