Archived Content

Cambridge Healthtech Institute's Fifth Annual
Protein-Protein Interactions
Targeting PPI for Therapeutic Interventions
April 18-19 

Day 1 | Day 2
Download Drug Discovery Chemistry Brochure or Protein-Protein Brochure 

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

 

THERAPEUTIC APPLICATIONS 

1:30 Chairperson’s Opening Remarks

Andrei Gartel, Ph.D., Associate Professor, Medicine, University of Illinois

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
Biorad
3:10 Lead Discovery: Screening and Characterization Using Multiplexed SPR

Olan Dolezal, Ph.D., Senior Research Scientist, CSIRO (the Commonwealth Scientific and Industrial Research Organization), Australia

 

Sponsored by
Selcia logo small
3:25 Capillary Electrophoresis : an Ideal Solution-Based Method for Monitoring Protein-Protein Interactions

Carol Austin, Ph.D., Biology Group Leader, SelciaA number of protein-protein interactions (PPIs) are validated therapeutic targets however, the challenge is the availability of biophysical techniques suitable to detect weak affinity fragment inhibitors as novel starting points for this challenging target class. Capillary electrophoresis (CE) can readily detect PPIs in solution, without the need to tether either protein and inhibition using weak affinity fragments can be detected.  Examples of PPI CE assays will be presented.

 

3:40 Networking Refreshment Break in Exhibit Hall with Poster Viewing

 

DRUGGABILITY OF PPI 

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

In this interactive session, several topics will be offered for discussions and delegates are invited to choose a breakout topic of interest and join the moderated discussion at hand. In this informal setting, participants are encouraged to share examples from their work, vet ideas with peers and be part of a group problem-solving endeavor. We emphasize that this discussion is an informal exchange amongst scientists and is not meant to be, in any way, a product discussion.

Topic: Modeled Structures as Drug Targets

Moderator: Ilya Vakser, Ph.D., Director and Professor, Bioinformatics, University of Kansas

  • Docking of modeled proteins
  • Ligand pockets on modeled PPI interfaces
  • Ligand docking to modeled receptor sites

Topic: Protein-protein Interactions: Druggability and Chemical Space

Moderator: Sandor Vajda, Ph.D., Professor,Biomedical Engineering and Chemistry, Boston University

  • What is common among protein-protein interaction (PPI) targets that are amenable to inhibition by small molecules?  Are there different classes among such PPIs? In what areas do you expect some success first? What fraction of the known PPIs is expected to be druggable?
  • What are the requirements for druggability? Do they differ from those for the druggability of traditional drug targets?  What types of thermodynamic, structural, or biochemical data can help to assess druggability?
  • What is common among inhibitors of PPIs? Do they have any specific structural or chemical characteristics? Are peptides or macrocyclic compounds potentially useful as inhibitors?
  • What tools can be useful for finding hits for PPI targets? Will HTS or virtual HTS campaigns play potentially important roles? Are screening libraries appropriate to perform HTS (virtual or real) of PPI targets? How to develop libraries that are potentially more useful for a specific PPI target? How to develop libraries that are potentially more useful for PPI targets in general?
  • What is the potential of fragment-based approaches to finding hits? What method can be used for fragment screening? Is there anything special about PPI targets in this context?

Topic: PPI - Current Challenges

Moderator: Philippe Roche, Ph.D., Senior Scientist, Cancer Research, CNRS

  • Druggability of protein-protein interactions
  • How to define chemical libraries dedicated to PPIs?
  • Is the Ro5 a barrier to further PPI inhibitors development?
  • What is the potential of PPI inhibitors to lead to marketed drugs?

6:30 End of Day



Day 1 | Day 2
Download Drug Discovery Chemistry Brochure or Protein-Protein Brochure