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Wednesday, April 28
12:30 pm Registration
1:30 Chairperson's Opening Remarks
1:40 Small Molecule Inhibitors of Protein-Protein Interactions: The Importance of Three-Dimensionality
David C. Fry, Ph.D., Senior Research Leader, R&D Discovery Chemistry, Roche
2:10 Design, Synthesis and Evaluation of New Monovalent BIR2-Selective Inhibitors of the Anti-Apoptotic Protein XIAP
Nicholas Cosford, Ph.D., Associate Professor, Apoptosis and Cell Death Signaling, Burnham Institute for Medical Research
Defects in apoptosis (programmed cell death) lead to uncontrolled cellular proliferation in cancer. X-linked inhibitor of apoptosis protein (XIAP) inhibits apoptosis by binding to caspases. Using structure-based design we synthesized small molecule XIAP inhibitors which led to the identification of new compounds that selectively bind to the BIR2 domain of XIAP . In addition to enabling our understanding of the cellular mechanisms of apoptosis, these small molecules are potential leads for the development of new cancer therapeutics.
2:40 Discovery of Protein-Protein Interaction Inhibitors through HTS
Haian Fu, Ph.D., Professor, Pharmacology; Director, Emory Chemical Biology Discovery Center, Emory University School of Medicine
The Emory Chemical Biology Discovery Center has a particular focus on targeting protein-protein interactions through high throughput screening for small molecule modulator discovery. Targeted protein pairs include 14-3-3/Raf-1 in cell proliferation pathway, ERalpha/co-activator in estrogen signaling, eIF4E/4G in translational control, and Mcl1/Noxa in apoptosis. A case study will be presented to illustrate the discovery of small molecule protein-protein interaction inhibitors.
3:10 Structure Based Design of PDE4 Allosteric Modulators with Improved SafetySponsored by
Alex Burgin, COO, Emerald BioStructures
PDE4 is the primary cAMP hydrolyzing enzyme in cells and an important therapeutic target for inflammatory and CNS indications; however, no PDE4 inhibitor has been approved because of dose limiting side effects. We have obtained the first crystal structures of PDE4B and PDE4D regulatory domains interacting with the catalytic domain. We have used these structures to create allosteric modulators which mediate a specific protein:protein interaction within PDE4. Modulators which exploit this unique mode of action are more selective because of sequence differences within the regulatory domain. Allosteric modulators are also noncompetitive with cAMP and only partially inhibit biological isoforms. As a result of these unique features, allosteric modulators have significantly improved safety profiles compared to traditional PDE4 inhibitors. We will describe the technologies and approaches that enabled this discovery and how this new approach may be applicable to other phosphodiesterases and other enzyme families.
3:25 Sponsored Presentations (Opportunity Available)
3:40 Networking Refreshment Break, Poster and Exhibit Viewing
4:20 Discovery of Novel Tetrahydroisoquinoline Derivatives as Bcl-2 Inhibitors
John Porter, Ph.D., Senior Principal Scientist, UCB Celltech
Bcl-2 functions as an anti-apoptotic protein by forming protein-protein interactions with other family members preventing their oligomerization and the initiation of the apoptosis cascade. Small molecules that can disrupt this protein-protein interaction should allow the recovery of the apoptotic mechanism. Bcl-2 is over expressed in a number of human cancers and so forms an attractive target for therapuetic intervention. This talk will describe the discovery of a series of novel Bcl-2 inhibitors that appear to function through conformational constraints exerted by their tetrahydroisoquinoline scaffold.
4:50 FRET-Based Determination in Living Cells of the Stoichiometry and Geometry of Some GPCR Homo-Oligomers in the Presence and Absence of Ligands
Valerica Raicu, Ph.D., Associate Professor, Physics; Biological Sciences, University of Wisconsin-Milwaukee
Advances in instrumentation and the theory of Förster Resonance Energy Transfer (FRET) recently lead to our development of a novel method for the determination of the stoichiometry, structure, and localization in living cells of membrane protein complexes (Raicu et al., Nature Photonics, 3, 2009). This presentation will review the results obtained from our recent studies of oligomeric complexes of some G protein-coupled receptors (GPCRs) in vivo, both, in the presence and in the absence of natural as well synthetic ligands.
5:20 Break-Out Discussions
6:30 End of Day
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