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Day 1 - Protein-Protein Interactions As Drug Targets

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12:30 pm Registration


1:30 Chairperson’s Opening Remarks
Ruben Abagyan, Ph.D., Professor, Department of Molecular Biology, The Scripps Research Institute, La Jolla

1:40 Targeting the Eph/ephrin Interaction

Jill E. Chrencik, Ph.D., Principal Scientist, Department of Computational and Structural Biology, Pfizer Global Research and Development, St. Louis
The Eph family of receptor tyrosine kinases and their ligands, the ephrins, regulate numerous biological processes in developing and adult tissues, and have more recently been implicated in cancer progression and in pathological forms of angiogenesis. Here we present the 1.65-Å crystal structure of the ligand binding domain of EphB4 in complex with an antagonistic peptide that inhibits ephrinB2 binding and exhibits anti-tumorigenic properties in vivo. Further, we present the 1.9-Å crystal structure of the EphB4/ephrinB2 complex and the 2.1-Å crystal structure of the EphB2/SNEW antagonistic peptide complex, revealing how subtle differences in the amino acid composition of the conformationally flexible loops for both the EphB4 and EphB2 receptors results in the recruitment of a unique set of ligands to the cell surface. The detailed structural information and the tool peptides provide an opportunity for the systematic identification of small-molecule inhibitors for Eph/ephrin PPIs.

2:10 Protein-Protein Interactions in HCV as New Targets for Drug Discovery
A. Donny Strosberg, Ph.D., Professor, Department of Infectology, The Scripps Research Institute-Florida
Homo-dimerization of HCV core protein is essential for assembly of the viral nucleocapsid. We have designed assays to monitor this protein-protein interaction. Using both HTRF and Alpha formats we have identified a 15-residue core-derived peptide which inhibits dimerization of a 106 residue fragment of core, (IC50=22 micromolar) and blocks infectious HCV release from host hepatoma cells. Modified versions of this peptide may serve as high-affinity inhibitors of HCV. Additionally, non-peptidic inhibitors identified in large libraries of chemical compounds using our assays will also be evaluated for their effect on the propagation of infectious HCV.

2:40 Targeting Protein Interactions to Identify Therapeutic Agents in Huntington’s Disease and Other Neurodegenerative Diseases
Sudhir Sahasrabudhe, Ph.D., Chief Scientific Officer, Prolexys Pharmaceuticals
The neurotoxicity observed in Huntington’s disease (HD) may be a consequence of protein interactions involving mutant huntingtin (Htt) protein. We identified a comprehensive set of Htt interactors using two complementary approaches: high-throughput yeast two-hybrid screening and affinity pull down followed by mass spectrometry. A subset of these genes were tested for their role as genetic modifiers of neurodegeneration in a Drosophila model of HD. Interacting proteins confirmed as modifiers represent a diverse array of biological functions, including synaptic transmission, cytoskeletal organization, signal transduction, and transcription. These studies demonstrate that high-throughput screening for protein interactions can result in the identification of candidate targets. Furthermore, a set of disease-related proteins common to multiple neurodegenerative disorders provide an opportunity to identify therapeutic agents that are effective against a broad spectrum of disorders that involve neuronal cell death.

3:10  Predicting and Optimizing Protein-Protein Interactions in Discovery Studio
Dipesh Risal, Ph.D., Product Manager, Life Sciences, Accelrys


Predicting protein-protein interactions is critical to success in many therapeutic research areas such as antibody modeling, elucidation of signal transduction pathways, and identification/optimization of peptide or protein inhibitors or activators for drug discovery. Accelrys provides a complete suite of tools for protein-protein docking, beginning with sequence analysis, leading to homology modeling using MODELER, and finally protein-protein docking, refinement, and scoring using ZDOCK/RDOCK and CHARMm. We will demonstrate the use of these tools in the docking and refinement of the proteins involved in the MutHLS DNA mismatch repair mechanism. The results will be compared to an experimental study in which protein interaction sites between MutH and MutL were identified using a combination of site-directed mutagenesis and site-specific cross-linking.

3:25 Networking Refreshment Break, Poster and Exhibit Viewing

4:05 Lead Identification Strategy for Compounds that Disrupt KEAP1:NRF2
J. Fred Hess, Ph.D., Senior Investigator, Neuroscience Drug Discovery, Merck Research Laboratories
Oxidative stress is a pathogenic mechanism that has been implicated in a variety of diseases. The transcription factor Nrf2 regulates the expression of a number of genes that encode components of cellular anti-oxidant defense systems. Activation of the Nrf2 pathway can be achieved by disrupting the interaction between Keap1 and Nrf2. X-ray crystallography of the kelch domain of Keap1 bound to a peptide derived from Nrf2 reveals specific molecular contacts that participate in this interaction. A variety of strategies have been employed, and assays have been developed, to identify lead compounds that disrupt the interaction between Keap1 and Nrf2.

4:35 BRCT(BRCA1)-Phosphoprotein Interactions as a Target for Breast Cancer Therapy
Amarnath Natarajan, Ph.D., Assistant Professor, Chemical Biology Program, University of Texas Medical Branch
The C-terminus domains of BRCA1 (BRCT) interact with a variety of other proteins (Abraxas/BACH1/CtIP) to facilitate cellular functions such as checkpoint regulation, DNA damage response, and DNA repair. Mutations found in the BRCT (BRCA1) result in the formation of tumors in the breast and ovarian tissues. These mutations genetically predispose women to breast and ovarian cancers. However, retrospective clinical studies show that patients with mutations in the BRCT domains respond better to chemotherapy. The molecular basis for the cancer caused by the M1775R mutant protein has been attributed to the loss of BRCTM1775R binding to proteins, Abraxas/BACH1/CtIP. Using a combination of cell-free and cell-based assays we identified small-molecule inhibitors of the BRCT(BRCA1)-phosphoprotein interaction. We also show that BRCT(BRCA1) inhibitors sensitize breast cancer cells to growth inhibition and apoptosis induced by etoposide and bleomycin. Together, we propose that mimicking loss of function BRCT mutation by inhibiting the BRCT-mediated protein-protein interaction will sensitize wild-type breast and ovarian cancers to DNA damage-based therapeutics.

5:05 Targeting the RUNX1 Runt Domain – CBFß Interaction in Leukemia
John H. Bushweller, Ph.D., Professor, Dept. of Molecular Physiology & Biological Physics and the Dept. of Chemistry, University of Virginia
The t(8;21), fusing AML1 to ETO, is found in more than 12% of patients with acute myeloid leukemia (AML). We have initiated a program of inhibitor development targeting critical protein-protein interactions of AML1-ETO. We have used a mouse model of t(8;21) leukemia to show that disruption of its interaction with CBFβ is a valid therapeutic approach. We have developed initial lead compounds for this target using virtual screening of the CBFβ binding site on the AML1 Runt domain. Initial leads were optimized using a rational medicinal chemistry approach to generate structure-activity relationships (SAR), resulting in compounds with low μM IC50 values for our best current leads. For the most potent compound to-date (IC50 = 2 µM), we have shown that it is bioavailable and can disrupt the Runt domain-CBFβ interaction. Our recent results show that treatment of t(8;21) cell lines with this compound results in blockage of proliferation, increased apoptosis, and increased differentiation.

5:35 End of Day

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