9th Annual

Protein-Protein Interactions

Targeting PPIs for Therapeutic Interventions

April 19-20, 2016

Protein-Protein Interactions icon  

Many important biological processes are controlled by protein complexes comprised of protein-protein interactions (PPIs). Thus PPI sites represent potential targets for compounds to be developed against for modulation of specific disease processes. Such modulator compounds however are difficult to discover and design because unlike typical drug compounds, they are not easily screened for because they are not  designed to inhibit the catalytic site of an enzyme. However advances in adapting biophysical approaches to higher-throughput formats for detecting protein-protein interactions have enabled progress. An increase in the types of easily screenable compounds (such as macrocyclic peptides from DNA-encoded libraries) that can cross the cell membrane and reach intracellular PPI targets has also spurred the field forward. This meeting covers progress in the PPI area with a focus on how scientists have dealt with the challenging questions in PPI-targeted drug design such as: should we inhibit the PPI directly or allosterically? Which interface should be targeted and how much of it? Should the inhibitor bind transiently or longer?

Final Agenda

Day 1 | Day 2 | Download Brochure

Tuesday, April 19

7:00 am Registration and Morning Coffee


8:00 Chairperson’s Opening Remarks

Kevin Lumb, Ph.D., Scientific Director, Discovery Sciences, Janssen R&D

8:10 Conformation-Selective Inhibitors of the AAA ATPase p97

Stacie_BulferStacie Bulfer, Ph.D., Post-Doctoral Scholar, Michelle Arkin Laboratory, Pharmaceutical Chemistry, University of California, San Francisco

The AAA ATPase p97 interacts with many adaptor proteins to function in a diverse set of cellular processes that regulate protein homeostasis. Because of p97’s role in protein homeostasis, specifically ERAD and autophagy, it has emerged as a drug discovery target for both cancer and neurodegeneration. This talk will describe the discovery and development of an allosteric, conformation-selective inhibitor of p97.

8:40 The Discovery of CB-5083: A First-In-Class Inhibitor of p97 for the Treatment of Cancer

Han-Jie_ZhouHan-Jie Zhou, Ph.D., Senior Director of Chemistry, Cleave BioSciences

This talk will describe techniques used to discover CB-5083, a potent and selective p97 inhibitor with good pharmaceutical properties currently in Phase I clinical trials against solid tumors and hematological malignancies. The inhibition of the D2 ATPase activity of p97 prevents effective protein-protein interactions which play an important role in protein homeostasis mechanisms. A variety of biochemical, cellular and in vivo data supporting CB-5083’s selection as a development candidate will be presented.

9:10 Applying the Compound-to-Target™ Platform to PPI Research

Ramon Jimenez-Moreno, Ph.D., Head, Biology, ASINEX Corporation

Making the step from conceptual design to drug discovery candidate is one of the most challenging tasks in drug discovery, especially when one addresses “difficult” or “challenging” targets. At Asinex, we have developed the Compound-to-Target™ platform to efficiently allocate the use of early drug discovery resources in developing tool compounds, hits, leads, and candidates. In this talk, we will relate efficiencies of this platform and show an example of this via our PPI research.

9:40 Coffee Break

10:05 A New Paradigm in Drug Action: Differentiated Gain of Function amongst IMiD® Analogues Binding the E3 Ubiquitin Ligase, CRL4CRBN

Philip Chamberlain, Ph.D., Principal Scientist, Biochemistry and Structural Biology, Celgene

Cereblon is a substrate receptor for the CRL4 ubiquitin ligase. Drugs such as lenalidomide and pomalidomide bind cereblon and trigger the recruitment of substrate proteins for ubiquitylation and degradation. In this presentation we will describe mechanistic and structural studies aimed at discovery of next-generation cereblon modulators.

10:35 Discovery and Characterization of Small Molecule Fragments that Bind and Inhibit the Ubiquitin Specific Protease 7 (USP7)

Paola_Di_LelloPaola Di Lello, Ph.D., Scientist, Department of Structural Biology, Genentech

USP7 has recently emerged as an attractive oncology target because its inhibition stabilizes p53, thus promoting p53-dependent apoptosis in cancer cells. Using a multidisciplinary, fragment-based drug discovery approach we found small molecule ligands that, although binding USP7 in a region distinct from the catalytic site (the palm region), inhibit USP7 enzymatic activity. These compounds appear to inhibit USP7 by a novel mechanism of action based on the interference of the interaction between enzyme and substrate.

11:05 Structure-Based Targeting of De-Ubiquitinases (DUBs)

Chitta Das, Ph.D., Associate Professor, Biochemistry, Purdue University

11:35 Enjoy Lunch on Your Own

12:05 pm Session Break


1:15 Chairperson’s Remarks

Laura Silvian, Ph.D., Principal Scientist, Cell and Protein Sciences, Biogen

1:20 FEATURED PRESENTATION: From Fragment to in vivo Activity for a Challenging PPI Target: Discovery of Potent Inhibitors of Keap1-Nrf2 Interaction

Tom DaviesTom Davies, Ph.D., Associate Director, Molecular Sciences, Astex Pharmaceuticals

Keap1 is the key regulator of the Nrf2-mediated cytoprotective response, and a target for diseases involving excessive oxidative stress. Using a fragment-based approach we have developed a small-molecule antagonist KI-696 which combines tight and selective binding to the Keap1 Kelch domain with favourable physicochemical properties. KI-696 potently activates Nrf2 in cells and shows promising activity in in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the Kelch-Nrf2 interaction.

1:50 Optimization of Novel Bcl-2 Inhibitors

George_DohertyGeorge Doherty, Ph.D., Principal Research Scientist, Oncology Discovery, Abbvie
Many cancer cells maintain survival through over-expression of anti-apoptotic BCL-2 family proteins, making them compelling targets for the development of cancer therapeutics. However, disrupting the protein-protein interaction between these BCL-2 proteins and the pro-apoptotic BH3 proteins has been a major challenge for the field. The BCL-2/BCL-XL inhibitor ABT-263 (navitoclax) has shown promising activity in the clinic but its efficacy has been limited by thrombocytopenia caused by BCL-XL inhibition. This clinical result led to the design of ABT-199/GDC-0199, a BCL-2-selective inhibitor that maintains efficacy in hematologic malignancies while sparing platelets. The challenging path to ABT-199/GDC-0199 including additional efforts to further improve the pharmacokinetic properties of this series of molecules will be presented.

2:20 Efficient Small Molecule Inhibitors of the HDM2-p53 Protein-Protein Interaction

Michael_ReutershanMichael H. Reutershan, Senior Scientist, Medicinal Chemistry, Merck Research Laboratories.

This talk will describe efforts to design efficient, low molecular weight inhibitors of the HDM2-p53 protein-protein interaction with good physical properties and PK profiles. In particular, the optimization of a novel lead with modest HDM2 affinity into a highly efficient series of compounds without significantly increasing molecular weight will be described. Our strategy of utilizing conformational control and biostructural information to guide design while focusing on physical properties will be highlighted

2:50 Inhibitors of MAP Kinases Targeting a Novel Allosteric Site

Juan_Jesus_PerezJuan Jesus Perez, Ph.D., Professor, Department of Chemical Engineering, Technical University of Catalonia and Director, Molecular Modeling, Allinky Biopharma

Analysis of the crystallographic structure of the p38 MAP kinase-MK2 complex made us hypothesize that protein-protein interactions force p38 to be lock in its inactive conformation. To explore this hypothesis we considered a combined approach using modeling and medicinal chemistry to develop successfully small molecule inhibitors of this site.

3:20 Selected Poster Presentations 

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing


A Chemist's Foray into Translational Research

Peter SchultzPeter G. Schultz, Ph.D., Professor, Department of Chemistry, The Scripps Research Institute and Director, California Institute for Biomedical Research

Our research program combines the tools and principles of chemistry with the molecules and processes of living cells to synthesize new molecules and molecular assemblies with novel physical, chemical and biological functions. By studying the structure and function of the resulting molecules, new insights can be gained into the mechanisms of complex biological and chemical systems.

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

6:30 Close of Day

Day 1 | Day 2 | Download Brochure

Wednesday, April 20

7:30 am Continental Breakfast Breakout Discussions

In this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers. Check our website in February to see the full listing of breakout topics and moderators.

Topic: How/When to Embark on a Covalent Inhibitor Strategy

Moderator: Daniel A. Erlanson, Ph.D., Co-Founder, Carmot Therapeutics, Inc.

  • Include as part of the hit identification process?
  • Substrate-based approaches
  • PK considerations
  • Types of targets most or least amenable (ubiquitinated proteins?)
  • Reversible vs irreversible warheads

Topic: PPI Approaches for Ubiquitin Regulated Proteins

Moderator: Han-Jie Zhou, Ph.D., Senior Director of Chemistry, Cleave BioSciences

  • Which steps/proteins of ubiquitin process are good drug target
  • Progress on different targets
  • Challenges and best approaches for targeting ubiquitin-related processes

Topic: Challenges in Targeting PPIs

Moderator: Laura Silvian, Ph.D., Principal Scientist, Cell and Protein Sciences, Biogen

  • Screening methods, biophysics verses biochemical and their pros/cons
  • PPI Libraries
  • Lipinski dilemma, how to keep hits lean and mean
  • Is covalent the right way to gain a foothold?


8:30 Chairperson’s Remarks

Paola Di Lello, Ph.D., Scientist, Department of Structural Biology, Genentech

8:35 Triage of HTS Hits for Protein-Protein Interactions

Kevin_LumbKevin Lumb, Ph.D., Scientific Director, Discovery Sciences, Janssen R&D

The false positive rate for HTS can be high and strategies are required to identify bona fide hits from assay or compound artifacts. This can be especially true for protein-protein interaction screens with an obligate emphasis on through-space methods that report on disruption of the protein-protein interaction rather than substrate/product detection methods. The application of biophysical approaches to triage HTS hits will be described.

9:05 How to Facilitate the Identification of Protein-Protein Interactions Inhibitors

Oliver_SperandioOliver Sperandio, Ph.D., Senior Research Associate, Inserm

Using a chemoinformatics procedure we show that comparable classes of PPI targets can be formed using either the similarity of their ligands or the shared properties of their binding cavities. Such identified classes of targets can lead to the design of PPI-class specific chemical libraries and therefore facilitate the development of PPI modulators to the stage of drug candidates. We moreover show how these techniques can be used to reposition existing drugs to new therapeutic areas.

9:35 Coffee Break in the Exhibit Hall with Poster Viewing

10:30 Targeting Ras-GTPase Oncogenic Interactions and Other PPIs with Cyclic Peptides

Dehua_PeiDehua Pei, Ph.D., Professor, Department of Chemistry and Biochemistry, The Ohio State University

Protein-protein interactions (PPIs) are challenging targets for small-molecule drug discovery. Cyclic peptides can serve as effective PPI inhibitors in vitro, but they are generally impermeable to the cell membrane. We have discovered a novel class of exceptionally active cyclic cell-penetrating peptides (CPPs). Incorporation of these CPPs into cyclic peptides resulted in potent, selective, proteolytically stable, and cell-permeable inhibitors against a variety of intracellular proteins including calcineurin, CFTR-associated ligand, K-Ras, and PTP1B.

11:00 Chemokines and their Receptors: Structural Basis of a Key PPI in Immunity, Inflammation and Cancer

Irina_KufarevaIrina Kufareva, Ph.D., Project Scientist, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego

Chemokines are a family of 7-12 kDa secreted proteins that control cell migration in the context of development, immunity, inflammation, and cancer, all by virtue of their interaction with 7TM cell surface receptors. Inhibitors of receptor-chemokine interactions attract immense attention in several therapeutic areas. By a combination of molecular modeling, biophysical and functional experiments, and X-ray crystallography we elucidate the structural determinants of these interactions, with the goal of rationalizing the discovery of therapeutics targeting the chemokine receptor axis.

11:30 Protein-Protein Interactions at the Synapse: Development of a Potent PDZ-Domain Specific Inhibitor Using Structure-Based Drug Design

Laura_SilvianLaura Silvian, Ph.D., Senior Scientist, Cell and Protein Sciences, Biogen

In this study we describe development of a potent, non-peptide based inhibitor of the PICK1:AMPA receptor interaction and the efforts to screen for hits and structurally characterize its binding to the PICK1 PDZ domain in order to improve potency and selectivity. We describe here the multi-step method we used to produce a crystal structure of a ligand-bound PDZ domain, which is one of the first of its kind. We will present more generalized rules that we are learning about this type of protein-protein interaction to support development of new PDZ-domain inhibitors.

12:00 pm Close of Track

Day 1 | Day 2 | Download Brochure