Protein-Protein Interactions as Drug Targets header 

 

About This Conference:

Inhibiting protein-protein interactions (PPIs) is gaining ground in the drug discovery industry as a way to find new drug candidates either against previously intractable targets such as protein regulatory complexes or ‘tried and true’ targets such as kinases but where new options are needed. PPI approaches are in contrast to traditional drug discovery that focuses on indentifying direct inhibitors of an enzyme’s catalytic site. This meeting will provide examples of PPIs that are being targeted in the drug discovery industry, applications of new approaches for finding PPI inhibitors and some of the resulting drug development challenges.


Wednesday, October 8

7:00 am Registration and Morning Coffee


CASE STUDIES ON PPI TARGETS

8:05 Chairperson’s Opening Remarks

Pamela Williams, Ph.D., Director, Structural Biology, Astex

8:15 FEATURED PRESENTATION: Selective BCL-2 Family Inhibitors: Potential Therapeutics and Powerful Research Tools

Andrew SouersAndrew J. Souers, Ph.D., Project Director, 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 protein-protein interactions, such as the BCL-2 or BCL‑xL interactions with 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 will be presented, as will clinical data that represents validation of the hypothesis behind selectively targeting BCL-2 . While ABT-199/GDC-0199 has helped establish the importance of targeting BCL-2 in hematologic malignancies, expression of BCL-xL has been linked with drug resistance and disease progression in multiple solid tumors. Efforts towards the development of novel BCL-xL-selective inhibitors will also be discussed.

9:00 Dimethyl Fumarate and Activation of the Nrf2 Pathway via Keap1 Modification

Robert H. Scannevin, Ph.D., Director, Neurology Research, Biogen Idec

Delayed release dimethyl fumarate (DMF) is an approved oral therapy for multiple sclerosis. One of the primary DMF mechanisms of action is activation of the Nrf2 pathway by covalent modification of Keap1 and subsequent liberation of Nrf2 from constitutive degradation. Our current works focuses on understanding how differential modification of Keap1 influences interaction with Nrf2 and downstream gene transcription.

9:30 ERK- DNMT3A Interaction Epigenetically Regulates Gene Expression

Deepak Kumar, Ph.D., Senior. Scientist, TIP Immunology, EMD Serono

DNA methylation is one of the critical events that epigenetically regulate gene expression during various physiological and pathological conditions. We have found that FGF signaling via ERK1/2 not only phosphorylates de novo DNA methyltransferase, DNMT3A, but also blocks its recruitment and function in mesenchymal stem cells. Further understanding of ERK-DNMT3A interaction may provide us with a novel target to regulate gene expression.

10:00 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing


PEPTIDES FOR PPIs

10:45 Oral Peptide Therapeutics for Inflammatory Bowel Disease

Larry Mattheakis, Ph.D., Director, Biology, Protagonist Therapeutics

Protagonist is utilizing its platform & know-how on orally stable peptides to discover highly innovative and safe drugs against IBD (inflammatory bowel diseases) & IBS (irritable bowel syndrome) disease related targets. This opportunity is very well differentiated both against small molecules (SMs) and biologics since SMs do not offer a large enough binding foot print and therefore lack potency against these PPI targets, and antibodies/biologics cannot be delivered orally. An additional advantage is that most of our PPI targets are clinically validated through FDA approval of injectable antibodies.

11:15 Get Exposed: Cell-Permeable Peptide Modulators Targeting Wnt Signaling in Cancer Stemness with Anti-Tumoral Activities upon Systemic Delivery

Jörg Vollmer, Ph.D., Managing Director, Nexigen GmbH

The identification of inhibitors of protein-protein interactions is not trivial but allows the extension of the druggable target space. Novel and improved PPI screening systems such as Nexigen’s peptide screening combine a wide applicability among target protein classes, increased sensitivity, better reliability and high hit rates. Cell-permeable peptides identifiedby Nexigen’s screening engine allow intracellular targeting of the Wnt pathway resulting in anti-tumoral activities.

11:45 An Allosteric Switch for Pro-HGF/Met Signaling Using Zymogen Activator Peptides

Robert A. Lazarus, Ph.D., Principal Scientist, Early Discovery Biochemistry, Genentech, Inc.

Hepatocyte growth factor (HGF) binds Met, leading to cell proliferation, migration, and survival. By incorporating structural and mechanistic insights from trypsin-like serine proteases into a novel phage display selection, we establish a path for reversible allosteric activators of zymogen-like pro-HGF that selectively bind the trypsin-like activation pocket to stimulate Met signaling for tissue repair. This strategy is extendable to zymogen serine protease and protease-like targets.

12:15 pm Sponsored Presentations (Opportunities Available)

12:45 Session Break

1:00 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:40 Session Break


TARGETING PPIS: STRUCTURAL, FRAGMENT AND OTHER APPROACHES

1:50 Chairperson’s Opening Remarks

Robert H. Scannevin, Ph.D., Director, Neurology Research, Biogen Idec

 

2:00 Protein-Protein Interactions: An Easy Drug Target

Daria Mochly-Rosen, Ph.D., Professor, Chemical and Systems Biology, Stanford

Since 1991, we used a rational approach to identify peptide inhibitors of protein-protein interactions (PPI) as drugs in a variety of animal models of human diseases and in clinical trials. Over 40 peptides with select biological activities were designed and characterized for different signaling proteins. Two examples of the rational approach, the preclinical work and one clinical study with these PPI inhibitors will be discussed.

2:30 Fragment and Structural-Based Approaches for PPIs of Apoptotic Pathways

Pamela Williams, Ph.D., Director, Structural Biology, Astex

Fragment based drug discovery (FBDD) has been successfully used to identify hits for PPI targets, providing alternatives to more traditional methods like high-throughput screening or peptidomimetics. I will describe the use of FBDD to identify dual antagonists of XIAP and cIAP1, members of the inhibitor of apoptosis protein (IAP) family, key regulators of anti-apoptotic and pro-survival signalling pathways.

3:00 Sponsored Presentations (Opportunities Available)

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

4:10 Allosteric JAK Inhibition for Autoimmune Diseases

Atli Thorarensen, Ph.D., Associate Research Fellow, Immunoscience Research Chemistry, Pfizer

Selective target inhibition is a fundamental goal of drug discovery in order to deliver efficacy while sparing potential adverse side effects from off-targets. This talk will outline the strategy and results from phenotypic screening strategies using primary cells and in cell binding experiments that identified active, non-ATP competitive modulators for JAK.

4:40 Small Solutions for Big Problems: NMR as a Hit Generation Tool for PPIs

Edward R. Zartler, Ph.D., President & CSO, Quantum Tessera Consulting

Protein-Protein Interactions (PPIs) have great therapeutic promise, but are difficult targets to ligand. PPIs don’t have defined binding sites, instead having plastic binding interfaces. Fragment-based Hit Generation using NMR offers a robust avenue into this very difficult target class.

5:10 Interactive Breakout Discussion Groups

This interactive session provides conference delegates and speakers an opportunity to choose a specific roundtable discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion.

What Makes a Good PPI Target?

Kevin W. Hunt, Ph.D., Senior Research Investigator, Medicinal Chemistry, Array Biopharma

• Reactive sites?
• Depth of binding pocket?
• A bit of luck?

Bigger Molecules for PPI Targets

Robert A. Lazarus, Ph.D., Principal Scientist, Early Discovery Biochemistry, Genentech, Inc.

• Macrocyclics
• Peptides
•  Antibodies and other protein scaffolds

Combining New Methods for Probing PPIs

Pamela Williams, Ph.D., Director, Structural Biology, Astex

• Surface Plasma Resonance (SPR) screening
• NMR: non labeled v. fully labeled v. partially labeled proteins
• Computational approaches
 

6:10 Welcome Reception in the Exhibit Hall with Poster Viewing

7:15 Close of Day


Thursday, October 9

7:30 am Registration and Morning Coffee


EMERGING PPI TARGETS

8:00 Chairperson’s Opening Remarks

Daria Mochly-Rosen, Ph.D., Professor, Chemical and Systems Biology, Stanford

8:10 Targeting Protein-Protein Interactions: Novel Treatment for Neglected Tropical Diseases

Nir Qvit, Ph.D., Post-Doctoral Fellow, Chemical and System Biology, Stanford University

Based on rational approach we have developed novel peptide inhibitors of protein-protein interactions between LACK, scaffold Leishmania protein,and its binding proteins. The peptides inhibited promastigotes growth (IC50~10µM) and reduced in vivo parasitemia by 60%. Without any knowledge on partner proteins, we were able to design inhibitors of LACK’s function and affect the parasite’s viability. Our method is likely applicable to design other anti-parasitic drugs.

8:40 The Papillomavirus E1-E2 Interaction: a Surprisingly Druggable Target

Peter W. White, former Director, Infectious Disease at Boehringer Ingelheim

Inhibitors of protein-protein interactions could be one of the few options for treating conditions with no more obviously druggable targets. We identified inhibitors of the papillomavirus E1-E2 PPI by high-throughput screening, and a range of in vitro experiments were used to characterize them. Our experience may provide guidance for evaluating specific PPIs as drug targets and then for successfully identifying leads with potential for optimization.

9:10 Identifying Weak Protein-Protein Interactions

Richard R. Burgess, Ph.D., Professor Emeritus of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison

Important biological complexes are often dependent on weak protein-protein interactions with components that bind specifically but with low affinities or participate in transient interactions. Such weak PPIs, with T1/2’s of seconds, are often difficult or impossible to detect. This presentation discusses an innovative biochemical-based technology that relies on magnetic affinity beads and microfluidics to detect previously unseen weak PPI’s that may become important drug targets. 

9:40 Coffee Break in the Exhibit Hall with Poster Viewing


Targeting Ubiquitin Ligases
with PPI Approaches

10:30 The Discovery of Small Molecules Targeting the VHL E3 Ubiquitin Ligase and Disrupting Its Protein-Protein Interaction with HIF-alpha Subunit

Alessio Ciulli, Ph.D., Reader in Chemical & Structural Biology, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee

We have discovered drug-like small molecules that target the ubiquitin proteosome system by disrupting, with nanomolar potencies, the key interaction between the von Hippel-Lindau protein (VHL) cullin ring E3 ligase and with the Hypoxia Inducible Factor alpha subunit (HIF-α). Structure-based design informed by co-crystal structures and biophysical binding characterisation guided the medicinal chemistry optimization of our compounds. Our efforts combined peptidomimetic strategies with fragment-based deconstructive analyses.

11:00 Targeting the MDM2-p53 Protein-Protein Interaction for New Cancer Therapeutics

Shaomeng Wang, Ph.D., Director, Center for Discovery of New Medicines; Warner-Lambert/Parke-Davis Professor, Medicine, Pharmacology and Medicinal Chemistry, University of Michigan Comprehensive Cancer Center

Blocking the MDM2-p53 protein-protein interaction is being pursued as a new cancer therapeutic strategy. Our laboratory has designed and developed a class of highly potent and specific small-molecule inhibitors to block the MDM2-p53 PPI (MDM2 inhibitors). I will present our structure-based design and optimization of our MDM2 inhibitors and extensive preclinical studies of SAR405838 (MI-77301), which is now in phase I clinical development for the treatment of human cancers.

11:30 Enjoy Lunch on Your Own


1:00 pm Plenary Keynote Program 
 

Chas BountraChas Bountra, Ph.D., Professor of Translational Medicine & Head, Structural Genomics Consortium, University of Oxford

Martin TolarMartin Tolar, M.D., Ph.D., Founder, President & CEO, Alzheon, Inc.

Andrew L. Hopkins, Andrew L. Hopkins, D.Phil, FRSC, FSB, Chair of Medicinal Informatics and SULSA Research Professor of Translational Biology, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee


2:45 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 Close of Conference


Suggested Event Package:

October 7 Short Course: Targeting Protein-Protein Interactions 

October 7 Short Course: Introduction to Targeted Covalent Inhibitors 

October 8-9: Protein-Protein Interactions as Drug Targets Conference 

October 9-10: Cancer Metabolism Conference 

October 9 Dinner Course: Setting Up Effective Functional Screens Using 3D Cell Cultures 


*Separate registration is required


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2014 Discovery on Target Brochure  

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PREMIER SPONSORS 

Cellecta 

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SPONSORSHIPS & EXHIBITS 

The exhibit hall was sold out in 2013, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2014, contact:

Jon Stroup
Business Development Manager
781-972-5483
jstroup@healthtech.com 

2014 Discovery On Target CAG 

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CONFERENCES


October 8 – 9

Targeting Epigenetic Readers and
Chromatin Remodelers
 

Targeting the Ubiquitin Proteasome System  

Big Data Analytics and Solutions  

GPCR-Based Drug Discovery  

RNAi for Functional Genomics Screening
– Part 1
 

Protein-Protein Interactions as Drug Targets  

Antibodies Against Membrane Protein Targets
– Part 1
 


October 9 – 10

Targeting Histone Methyltransferases and Demethylases  

Screening Drug Transporter Proteins  

Maximizing Efficiency in Discovery  

GPCR-Targeted Therapeutics  

Genome Editing for Functional Genomics
Screens – Part 2
 

Cancer Metabolism  

Antibodies Against Membrane Protein Targets
– Part 2
 


SYMPOSIUM


October 7

Next Generation Histone Deacetylase Inhibitors  


SHORT COURSES


October 7

SC1: Designing Scalable Software Systems for Big Data Analytics  

SC2: Approaches for Biologically-Relevant Chemical Diversity  

SC3: Setting Up Effective RNAi Screens: From Design to Data to Validation  

SC4: Targeting Protein-Protein Interactions  

SC5: GPCR Structure-Based Drug Discovery  

SC6: Advances in Metagenomic Drug Discovery for New Anti-Infective Agents  

SC7: Targeting of GPCRs with Monoclonal Antibodies  

SC8: A Primer to Gene Editing: Tools and Applications  

SC9: Introduction to Targeted Covalent Inhibitors  


October 9

SC10: Setting Up Effective Functional Screens Using 3D Cell Cultures  

SC11: Integration of BDDCS and Extended Clearance Principles  

SC12: Introduction to Allosteric Modulators and Biased Ligands of GPCRs  

SC13: Introduction to Drug Metabolism