Cambridge Healthtech Institute's Fifth Annual
Protein-Protein Interactions
Targeting PPI for Therapeutic Interventions
April 18-19
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In its fifth year, CHI’s conference is covering the journey from identifying PPI interaction pairs all the way to successfully developing a PPI inhibitor. Along the way, many questions need to be answered and obstacles need to be addressed such as challenges the binding sites are presenting, modulation of PPI, predicting PPI modes identifying novel inhibitors and what can be done to target PPI successfully.
WEDNESDAY, APRIL 18
12:30 pm Registration
1:30 Chairperson’s Opening Remarks
1:40 Targeting FOXM1/NPM Interactions against Cancer
Andrei Gartel, Ph.D., Associate Professor, Medicine, University of Illinois
In this study, we showed that FOXM1 interacts with NPM in human cancer cells. We also found that knockdown of NPM leads to the down-regulation of FOXM1 protein level. In addition, we observed that following NPM knockdown human cancer and immortal cells lose the expression of FOXM1. And we also demonstrated that FOXM1 or NPM knockdown impair the ability of MIA PaCa-2 pancreatic cancer cells to form colonies in cell culture and to form tumors in vivo. Taken together, our data suggest that in cancer cells the interaction between FOXM1 and NPM is necessary for sustaining the level and localization of FOXM1 and it may be required for cancer progression.
2:10 Cognition Enhancement by Disruption of NR2B-Cdk5 Interactions by a Small Interfering Peptide Drug
James Bibb, Associate Professor, Psychiatry and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center
Cognition is a fundamental neurobiological process that allows organisms to acquire, store and retrieve information. The cognitive ability of humans is a species-defining feature that declines with advancing age and is impaired in many CNS disorders. Although numerous molecular and cellular mechanisms that underlie cognitive functions have been identified, no effective therapeutics are yet available. Here we report a crucial molecular mechanism that mediates learning and memory via the glutamatergic NMDA receptor subunit, NR2B. We find that NR2B surface levels are controlled in an activity-dependent manner through the Cdk5-dependent phosphorylation state of Ser1116 of the receptor. We demonstrate that disruption of interactions between NR2B and Cdk5 by a small drug-like interfering peptide potentiates NR2B biophysical function and enhances cognition in rats. Our results reveal a novel synaptic mechanism that may be targeted for the development of small molecules for the treatment of learning and memory deficits and as cognitive enhancers.
2:40 Mimicking the Hotspots at Protein-Protein Interfaces
Lidio Meireles, Ph.D., Scientist, Vertex Pharmaceuticals
Small-molecule inhibitors of protein-protein interactions can be designed by targeting the hotspots at protein-protein interfaces. In this talk, we present a general computational methodology and tool for molecular mimicry design and show its application to designing small-molecules that mimic the hotspots at protein interfaces.
Sponsored by
3:10 Antibody Screening and Characterization Using Multiplexed SPR
Ruben Luo, Ph.D., Product Manager, Bio-Rad Laboratories
Sponsored by
3:25 Capillary Electrophoresis : an Ideal Solution-Based Method for Monitoring Protein-Protein Interactions
Carol Austin, Ph.D., Biology Group Leader, Selcia
3:40 Networking Refreshment Break in Exhibit Hall with Poster Viewing
4:20 Finding Druggable Hot Spots in Protein–Protein Interfaces
Sandor Vajda, Ph.D., Professor, Biomedical Engineering and Chemistry, Boston University
We have developed computational fragment mapping to identify “hot spot” regions in protein-protein interfaces. The method accounts for protein plasticity, and finds energetically favorable sites for fragment sized probe molecules. Results are presented for a large number of PPI targets.
4:50 An Example of Challenging Chemical Space: Protein-Protein Interfaces
Philippe Roche, Ph.D., Senior Scientist, Cancer Research, CNRS
We have recently developed 2P2IDB, a hand-curated structural database dedicated to PPIs with known inhibitors that can be freely accessed at http://2p2idb.cnrs-mrs.fr. The detailed analysis of protein-protein and protein-inhibitor interfaces in terms of geometrical parameters, atom and residue properties, buried accessible surface area and other biophysical parameters has allowed us to extract some key interface descriptors to assess the druggability of PPIs [3]. Analysis of the small molecule inhibitors present in 2P2IDB led us to define the ‘rule-of-four’ as a guideline to characterize PPI inhibitors [2]. We have used machine learning approaches and a set a DRAGON molecular descriptors to develop an original protocol to design targeted chemical libraries dedicated to PPIs. The capacity of this tool to significantly improve the success rate during virtual screening campaigns has been demonstrated on bioassays selected from the PubChem database.
5:20 Breakout Discussions
6:30 End of Day
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