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Immediately preceding Structure-Based
Drug Design, June 15-16
Day 1
Sunday, June 11
6-7pm Early Conference
Registration
Monday, June 12
| 7:30am Registration, Morning Coffee |
Sponsored
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8:20 Chairperson's Opening Remarks
Dr. John Cuozzo, Director, Lead Discovery, Praecis Pharmaceuticals Inc.
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8:30
Investigations into Activin-Like Kinases
(ALKs)
Dr. Ann Boriack Sjodin, Senior Scientisth, Physical Biochemistry, Biogen Idec Inc. |
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9:00 PKCtheta a Therapeutic Target for Potential Treatment of Multiple Sclerosis
Dr. Subba Chintalacharuvu, Senior Research Scientist, Core Pharmacology Group,
Eli Lilly & Co.
Multiple sclerosis (MS) is thought to arise when autoimmune helper T cells attack the myelin sheath of the spinal cord and neurons, causing symptoms ranging from fatigue and vision problems to paralysis. Members of the protein kinase C
(PKC) family are expressed in many different cell types, where they are known to regulate a wide variety of cellular processes that impact on cell growth and differentiation, cytoskeletal remodeling, and gene expression in the response to diverse stimuli. In vivo studies of PKC
isozyme-selective knockout and transgenic mice have highlighted distinct functions of individual PKC in different aspects of immune responses, including development, differentiation, activation as well as survival of immune cells. PKCq has been implicated in signaling of T cell activation, proliferation, and cytokine production. We used
PKCq-deficient mice to investigate the potential involvement of PKCq in the development of experimental autoimmune encephalomyelitis, a prototypic T cell-mediated autoimmune disease model of the central nervous system (CNS). PKCq enzyme was necessary for T cell and macrophage infiltration and demyelination of the CNS, as well as production of inflammatory and pathogenic cytokines by a subset of helper T cells. These results underscore the importance of PKCq in regulation of multiple T cell functions necessary for the development of autoimmune disease. PKCq may serve as an attractive therapeutic target for treating autoimmune disease such as MS.
9:30 CIP, a Peptide Derived from P35 Specifically Inhibits Cdk5 Deregulation
Dr. Harish C. Pant, Laboratory Chief, CPR/LNC/NINDS/NIH, NIH
Cdk5 activity is tightly regulated in the nervous system and is essential for nervous system development and survival. It has been proposed that deregulation of cdk5 activity in the brain, by abnormal production of p25, a truncated, more active fragment of p35, can lead to deregulation of Cdk5 and hyperphosphorylated tau pathologies characteristic of AD brains in humans. We found a peptide derived from p35 of 125 amino acids residues, (CIP), specifically inhibits Cdk5 deregulation and tau hyperphosphorylation in cortical neurons.
10:00 Coffee Break, Poster Set-Up and Exhibit Viewing
10:45 Technology Watch
Beyond Ultra-HTS: Rapid Discovery of Novel Kinase Inhibitors by Affinity Selection from Giga-Compound DNA-Tagged Small Molecule Libraries
Dr. John Cuozzo, Director, Lead Discovery, Praecis Pharmaceuticals, Inc.
The growing number of validated kinase targets has challenged the pharmaceutical industry to accelerate the discovery of novel kinase inhibitors. To address this challenge, we have developed affinity-based selection methods to screen microgram amounts of target protein against small-molecule combinatorial libraries comprised of over one billion DNA-tagged compounds (DirectSelectTM). We have used our libraries to identify novel sub-micromolar inhibitors of p38a, Aurora A and AblT315I. We have also shown that addition of known ATP competitive kinase inhibitors to the selections allows us to identify active site binders and that we can determine compound selectivity directly from primary screens. |
Sponsored
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11:15 A Novel Function for
Beta-Arrestins: ERK-Dependent Modulation of Nuclear Receptor Activity
Dr. Fabrice Piu, Director of Chemical Genomics, ACADIA Pharmaceuticals Inc.
Beta-arrestins were originally identified as critical effectors of agonist-dependent internalization of receptors. Our work demonstrates that, in addition,
beta-arrestin 2 can stimulate the transcriptional activity of retinoid receptors, a class of ligand activated transcription factors. This event relies on the direct activation of the MAP kinase ERK2, providing a mechanistic basis for the modulation of nuclear receptor function by extracellular stimuli.
11:45 Docking and Virtual Screening to Protein Kinases
Dr. Claudio N. Cavasotto, Senior Research Scientist, Molsoft LLC
12:15pm Lunch on your own (Technology Workshop Sponsorship Available)
1:40 Chairperson's Remarks
1:45 FLT3 Antibody-Based Therapeutics for Leukemia
Dr. Yiwen Li, Group Leader, Experimental Therapeutics, ImClone Systems Incorporated
FLT3, a class III receptor tyrosine kinase, is expressed on the blasts in most cases of acute leukemia. Activating mutations of FLT3 are present in approximately 30% of acute myeloid leukemia (AML) patients and are associated with a poor prognosis. Antibodies represent a unique class of therapeutics because of their high specificity toward a defined target antigen. This presentation will highlight recent progress in the generation and development of anti-FLT3 antibodies and immunoconjugates as well as their therapeutic potentials in the treatment of human hematologic malignancies.
2:15 BCR-ABL Kinase Dynamics in Disease and Drug Resistance
Dr. Mohammad Azam, Instructor, BCMP, Harvard Medical School
In patients with chronic myeloid leukemia (CML), kinase domain mutations account for imatinib resistance in about 90% of cases. Mutations cause either a direct steric hindrance to drug binding or a conformational change that favors kinase activation, which therefore precludes imatinib binding. We have analyzed two dual Src-Abl kinase inhibitors, AP23464 and PD166326, for activity against 58 imatinib resistant BCR-ABL kinase variants. By both cytotoxicity assay and molecular modeling, we show that AP23464 inhibits an open, active kinase conformation, while PD166326 binds to an open although enzymatically inactive conformation. Both of these compounds remain potent against the majority of imatinib resistant variants, with the notable exception of T315I. Based on molecular modeling of resistance mutations, we tested structural variants of AP23464 designed to retain activity against T315I. Two compounds, AP23846 and AP23994, inhibited native and T315I variants of BCR-ABL with a potency of 400-600
nM.
2:45 Dual Inactivation of Src Kinase Lyn by
Cbp, via Phosphorylation and Ubiquitination
Dr. Evan Ingley, Group Leader, WA Institute for Medical Research, The University of Western Australia, Australia
We have identified an interacting Lyn kinase substrate Cbp (Csk binding protein) through yeast two-hybrid assays. Lyn binds Cbp via its SH3 domain and then phosphorylates Cbp at multiple sites including Y381 and Y409 that form high affinity binding sites for Lyn’s SH2 domain. Lyn also phosphorylates Y314 of Cbp to recruit Lyn's negative site Y508 phosphorylating kinase
Csk/Ctk, leading to down regulation of Lyn's kinase activity. Using a
phosphotyrosine-specific yeast two-hybrid system, that we developed, we identified the SH2 domains of Csk as well as that of SOCS1 as binding specifically to phosphorylated Y314 of
Cbp. We show SOCS1, which is induced by Lyn kinase activity, associates with Cbp to allow the ubiquitination and subsequent proteasomal degradation of Lyn.
3:15 Refreshment Break, Poster and Exhibit Viewing
4:00 Discovery of Potent and Orally Active Multitargeted Receptor Tyrosine Kinase Inhibitors
Dr. Yujia Dai, Research Investigator, Abbott Laboratories
Multitargeted kinase inhibitors with manageable adverse effects hold great promise as anticancer agents. We have discovered a series of inhibitors that potently inhibit all the RTKs of VEGFR and PDGFR families and display significant oral antitumor effect. The structure-activity relationships, pharmacokinetics profiles and antitumor effects of these inhibitors will be discussed in this presentation.
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4:30 Potent Anti-Angiogenic and Anti-Tumor Effects of EXEL-2880, an Orally Available Small-Molecule Inhibitor of HGF and VEGF Receptors
Dr. Alison Henry Joly, Senior Director Lead Discovery, Exelixis
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| The Spectrum Selective Kinase Inhibitor
(SSKITM) EXEL-2880 (XL880) is a potent inhibitor of HGF and VEGF receptor tyrosine
kinases, which are known to promote tumor growth, angiogenesis, invasion and dissemination. In pharmacodynamic studies EXEL-2880 results in a potent, long-lived and reversible inhibition of the HGF receptor (Met) and
VEGFR2/KDR. Following acute administration, EXEL-2880 causes a profound and rapid onset of disruption of the tumor vasculature and death of both tumor and endothelial cells. EXEL-2880 causes significant tumor growth inhibition and tumor cytoreduction in a broad panel of tumor models (breast, colorectal, lung cancer and
glioblastoma) following chronic and intermittent dosing. EXEL-2880 demonstrates potent anti-tumor and
anti-angiogenic activity in preclinical models and is the first dual
c-Met/VEGFR inhibitor to enter clinical development. |
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5:00 Happy Hour in the Exhibit Hall
6:00 End of Day
For more information, please contact:
Margit Eder, Ph.D., Conference Director
Phone: 781-972-5478 • E-mail: meder@healthtech.com
For exhibit and sponsorship information, please contact:
Suzanne Carroll, Manager, Business Development
781-972-5452 • scarroll@healthtech.com
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