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Thursday, April 29

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

DESIGN AND IDENTIFICATION

8:15 Chairperson's Opening Remarks

9:00 Protein-Protein Interfaces: Toward Focused Chemical Databases?

Philippe Roche, Ph.D., Interactions, Dynamics& Drug Design, Institut de Microbiologie de la Méditérannée (IMM); Centre National de la Recherche Scientifique (CNRS), CNRS-IMM

Our group is focusing on the analysis of the basic principles and parameters that govern protein-protein recognition and their inhibition. This fundamental research has permitted us to develop and propose innovating protocols targeting PPI inhibitions, such as the 2P2I approach. The main actual impediment in further PPI inhibitors development relates to the absence of specific chemical databases. This talk will present our dedicated protein-protein database, 2P2I(DB) and the potential chemical compounds that can be associated.

9:30 Rational Design, Synthesis and Characterization of Potent, Non-Peptidic Smac Mimics/XIAP Inhibitors as Proapoptotic Agents for Cancer Therapy

Pierfausto Seneci, Ph.D., Professor, Organic and Industrial Chemistry, CISI, University of Milan

Novel proapoptotic compounds acting by inhibiting the Smac-IAPs protein protein interaction have been designed, synthesized and characterized. Computational models and structural studies (crystallography, NMR) have elucidated the SAR of this class of inhibitors, and have permitted further optimization of their properties. In vitro characterization (XIAP BIR3 and linker-BIR2-BIR3 binding, cytotox assays, early ADMET profiling) of the compounds has been performed, identifying one monomeric and two dimeric leads currently undergoing in vivo evaluation.

10:00 Networking Coffee Break, Poster and Exhibit Viewing

10:45 Investigation of Protein-Protein Interactions by Combinatorial Domain Hunting - Squared (CDHsq)

Stefanie Reich, Ph.D., Senior Biologist, Department of Biology, Domainex, Ltd.

In order to develop effective and specific drugs and agrochemicals, it is necessary to understand the molecular basis of protein function, and to identify compounds (leads) which perturb this activity. This process can be efficiently accelerated by knowing the structure of the proteins and the interfaces of protein-protein interactions. We developed CDHsq specifically to identify clones that produce multi-milligram levels of soluble and stable recombinant protein of a core protein-protein complex, required for structural analysis, in a time- and cost-effective manner.

11:15 Identification of Small Molecule Inhibitors of Myc Oncoprotein Function

Lars-Gunnar Larsson, Professor, Microbiology, Tumor and Cell Biology, Karolinska Institute

We performed a cellular screen for inhibitors of protein-protein interactions between the Myc oncoprotein and its obligatory partner Max based on Bimolecular Fragment Complementation assay (BiFC). Among 15 identified compounds two were of particular interest; INMI selectively targets the N-Myc-Max interaction both in cells and in vitro, and “terminator of Myc” (ToM) targets Myc for destruction. Both molecules inhibit Myc-driven malignant transformation of cells and are potential lead molecules for drug development.

PROMISING APPROACHES

11:45 Peptides, Peptidomimetics for Modulation of Protein-Protein Interactions: Implications in Autoimmune Diseases and Cancer

Seetharama Satyanarayanajois, Assistant Professor, Basic Pharmaceutical Sciences, University of Louisiana at Monroe

Protein-protein interactions play a major role in several cellular processes, including adhesion between cells for immune response, tight junctions that hold the blood-brain barrier, and signal transduction. Inhibition of protein-protein interaction has tremendous impact on understanding the structural basis of these interactions and in developing new therapeutic strategies for many human diseases. Our research interest is in area of peptide based drug-design as a promising approach for developing therapeutic agents for autoimmune diseases, inflammatory diseases and cancer.

12:15 Sponsored Presentation (Opportunity Available)

12:30 Walk and Talk Luncheon in the Exhibit Hall (Last Chance for Poster and Exhibit Viewing)

1:55 Chairperson's Remarks

2:00 Development of Small Molecules Targeting Menin-MLL Interaction in Leukemia

Jolanta Grembecka, Assistant Professor, Pathology, University of Michigan

The interaction of menin with MLL fusion proteins has been validated as a new therapeutic target for leukemias with MLL translocations. Using both the fragment-based screening and HTS we identified several different classes of compounds which interact with menin and inhibit menin interaction with MLL fusion proteins, both in vitro and in human leukemia cell lines. Medicinal chemistry efforts are underway to convert these compounds into new potential drug candidates for leukemia treatment.

2:30 Using Semi-Rational Design and Protein Folding to Engineer Highly Specific Protein-Protein Interactions for Therapeutic Intervention

Jody Mason, Lecturer, Biological Sciences, University of Essex

Disrupting protein-protein interactions that are implicated in pathogenic events has the potential to cure countless deadly diseases. We are screening short peptide libraries using an assay we have developed to generate highly specific antagonists that bind and sequester key targets that include amyloid sequences and transcription factors. Our initial sequences are establishing rules for de novo design of stable and specific peptide-based drugs. A variety of in vitro and in vivo techniques are used to characterise the peptides for efficacy.

3:00 Networking Refreshment Break

3:20 Control PPI Process Complexity with a Genealogical Database Model

Bill Harten, CEO, CTO, UNIConnect

PPI processes are highly complex and difficult to capture in a database. We have discovered that the data model for tracking and connecting people in a genealogical database is an excellent fit for tracking and connecting samples in the laboratory. This model allows for reruns, re-queueing of samples and process changes. It also tracks samples moving from container to container as they move through multiple steps, various instruments and move across multiple plates in different well positions.

3:50 Finding Druggable Sites and Fragment Hits for Protein-Protein Interaction Targets

Sandor Vajda, Ph.D., Professor, Biomedical Engineering, Boston University

We describe a method based on computational fragment mapping to identify “hot spot” regions in protein-protein interfaces. The method places molecular probes – small molecules or functional groups – on the protein surface, accounts for protein plasticity, and finds and clusters the energetically favorable sites for a variety of probes. Results are presented for a number of protein-protein interaction targets, including interleukin-2, Bcl-xL, MDM2, HPV-11 E2, ZipA, TNF-a, and NEMO. The method also predicts a number of functional groups that are likely to bind to the hot spot regions identified.

4:20 Coordinate Regulation of Multiple Biochemical Pathways by the Intersectin Scaffold

John O'Bryan, Assistant Professor, Pharmacology, University of Illinois College of Medicine

One of the greatest challenges faced by all organisms is cellular communication. Activation of cell surface receptors stimulates a myriad of pathways controlling growth, differentiation, development, and apoptosis. The function of these receptors is mediated by adaptor or scaffolding proteins which consist predominantly of protein:protein interaction domains. The intersectin scaffold represents one such regulator of receptor signaling. We will discuss the role of intersectin in compartmentalized signaling and the involvement of these pathways in physiological and pathological processes, including neuron survival and cancer.

4:50 End of Conference

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