9th Annual

Protein-Protein Interactions

Targeting PPIs for Therapeutic Interventions

April 19-20, 2016

 

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

Tuesday, April 19

7:00 am Registration and Morning Coffee

MODULATING PROTEIN-PROTEIN INTERACTIONS IN THE UBIQUITIN PATHWAY

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 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 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 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

PPI INHIBITORS IN DEVELOPMENT

1:15 Chairperson’s Remarks

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

1:50 Optimization of Novel Bcl-2 Inhibitors

George 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 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 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

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

6:30 Close of Day

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.

IDENTIFYING AND OPTIMIZING MODULATORS OF PROTEIN-PROTEIN INTERACTION SITES

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 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 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 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 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 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

Small Molecule and Macrocyclic Approaches

April 19-20, 2016  

This meeting features medicinal chemistry-focused case studies of small molecule drug candidates that are being tested in preclinical and early-phase clinical trials for inflammation-related conditions. Because the most recent ‘market’ successes for oral, anti-inflammatories have been against the intracellular janus kinases (JAKs), updates on progress of new and 2nd generation intra-cellular kinase inhibitor candidates will be covered. But drug leads directed against non-kinase targets such as nuclear receptors involved in innate immunity, will also be a part of the meeting. 

Tuesday, April 19

7:00 am Registration and Morning Coffee

INHIBITING PRO-INFLAMMATORY PATHWAYS: RORγ AND OTHER TARGETS

8:00 Chairperson’s Opening Remarks

Eric Schwartz, Ph.D., Executive Director, Medicinal Chemistry, Celgene

8:40 Quinoline Tertiary Alcohols as Modulators of Retinoic Acid Receptor-Related Orphan Receptor gamma t (RORγt)

Hari Venkatesan, Ph.D., Principal Scientist, Discovery Chemistry, Immunology, Janssen Research & Development

Differentiation of naïve T-cells into IL-17 producing Th17 cells is regulated by the nuclear receptor transcription factor retinoic acid receptor-related orphan receptor gt (RORgt). Blocking the production of pro-inflammatory cytokines by RORgt modulation has the potential to be a first-in-class treatment of autoimmune diseases. High-throughput screening identified a promising series of quinoline tertiary alcohols. The subsequent optimization efforts that resulted in the identification of compounds for in vivo profiling will be discussed.

9:10 Highly Selective and Cell-potent ASK1 Inhibitors 
Christoph Zapf, Ph.D., Senior Principal Scientist, Worldwide Medicinal Chemistry, Pfizer Research Labs

9:40 Coffee Break

10:05 Inducing RORgamma-Specific Inverse Agonism Using a Synthetic Benzoxazinone Ligand

Doug Marcotte, Associate Scientist, Physical Biochemistry, Biogen

RORγ regulates transcriptional genes involved in production of pro-inflammatory interleukin IL-17 which is linked to autoimmune diseases. We have discovered a series of synthetic benzoxazinone ligands having either an agonist (BIO592) or inverse agonist (BIO399) mode of action. We demonstrate that upon binding of BIO399 the AF2 helix of RORγ become destabilized. The X-ray structures of RORγ with BIO592 and BIO399 demonstrates how small modifications modulate the mode of action for achieving RORγ-specific inverse agonism.

10:35 Small Molecule Inhibitors of RORgamma and IRAK4 for the Treatment of Autoimmune Disorders

Susanta Samajdar, Ph.D., Director, Medicinal Chemistry, Aurigene Discovery Technologies Limited

Although biologics such as anti-TNFα antibody are fairly successful in the treatment of autoimmune disorders, there is significant unmet need due to heterogeneity in diseases and lack of response to established therapies in some patients. While biologics typically target one cytokine signaling pathway, small molecule therapeutics directed towards intracellular target(s) can interfere in the signaling from multiple cytokines potentially leading to improved response. Development of small molecule oral inhibitors of IRAK4 and RORgamma to target TLR/IL-R and Th17 pathway respectively will be discussed.

11:05 Structure-Based Design of Macrocyclic IL-17A Antagonists

Shenping Liu, Ph.D., Associate Research Fellow, Structural Biology and Biophysics, Pfizer Global Research and DevelopmentI

IL-17A is a pro-inflammatory cytokine that has been implicated in many autoimmune and inflammatory diseases. Monoclonal antibodies targeting the IL-17A pathway have shown significant efficacies in treating psoriasis and Psoriatic arthritis in late stage clinical trials, and one of them was approved recently. We are interested in developing small molecule IL-17A antagonists for oral medication. We have determined several IL-17A/antagonists complex structures. These structures enabled us to design macrocyclic IL-17A antagonists with much improved potencies.

11:35 Enjoy Lunch on Your Own

12:05 pm Session Break

INTRACELLULAR KINASE INHIBITORS FOR INFLAMMATION

1:15 Chairperson’s Remarks

Jennifer Venable, Ph.D., Associate Scientific Director, Medicinal Chemistry, J&J

1:20 Discovery of Potent, Selective, and Non-Covalent BTK Inhibitors for Clinical Development

Wendy B. Young, Ph.D., Vice President, Discovery Chemistry, Genentech

We developed a series of highly potent, selective, non-covalent Btk inhibitors that are efficacious in several rodent models of RA and lupus. Compounds in this chemical series remain highly active against the C481S Btk mutant identified in patients that have relapsed on Imbruvica®. We describe the SAR, preclinical DMPK and toxicology investigations leading up to the discovery and selection of our lead clinical candidate, GDC-0853. Results from our Phase 1 clinical trials will be shared.

1:50 A Covalent BTK Inhibitor for Inflammation

Eric Schwartz, Ph.D., Executive Director, Medicinal Chemistry, Celgene

This presentation will discuss the identification and characterization of a covalent BTK inhibitor with in vitro, in vivo and preliminary toxicity data presented.

2:20 BTK and other Case Studies: Fragment Hit Prioritization and Optimization for Immunology Targets

Jason Pickens, Ph.D., Senior Scientist, Medicinal Chemistry, Takeda

As cutting-edge methods for fragment screening evolve into a series of best practices, the question of how to prioritize fragment hit sets to select the “best” fragments for initial chemistry follow-up elicits wide-ranging levels of analysis and opinion among FBDD practitioners. Through select case studies of immunology targets including BTK, this presentation will illuminate some specific strategies employed recently by medicinal chemistry teams at Takeda California in the pursuit of high-quality drug candidates derived from fragment starting points.

2:50 Structure-Activity-Relationships around Lead Series of Selective Jak1 Inhibitors for Inflammation

Michael L. Vazquez, Ph.D., Associate Fellow, Medicinal Chemistry, Pfizer, Inc.

Our research efforts have identified a series of potent and selective JAK1 inhibitors. Our lead, PF-04965842, is currently in clinical trials for the treatment of autoimmune diseases. This talk will discuss learnings from our clinical experience with tofacitinib a pan-JAK inhibitor with respect to potency and selectivity, SAR, the preclinical evaluation of our lead, and crystallographic data which has enabled us to build a structural hypothesis for the JAK1 selectivity.

3:20 Selected Poster Presentations

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

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

6:30 Close of Day

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.

TREATING DISEASE-SPECIFIC INFLAMMATION

8:30 Chairperson’s Remarks

Kamal Puri, Ph.D., Senior Principal Scientist, Immunology & Inflammation, Celgene Corp. 

8:35 PTG-100: An Oral Peptide Antagonist of α4β7 Integrin for Ulcerative Colitis

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

PTG-100 is an oral peptide antagonist of the gut homing integrin α4β7. Its potency and selectivity are similar to that of the FDA-approved antibody vedolizumab. PTG-100 was chemically engineered to be orally stable within the harsh proteolytic and reducing environment of the human gastrointestinal tract. In preclinical animal models, PTG-100 exposure is largely restricted to GI tissues, whereby it alters the trafficking of gut homing T cells to reduce local inflammation. Together, these results provide the rational for investigating PTG-100 in human trials, specifically ulcerative colitis.

9:05 ATPase Modulators for Treating Inflammatory Bowel Disease

Alexander (Sandy) Hurd, Ph.D., Associate Director of Chemistry, Chemistry, Lycera Corp

Autoimmune diseases occur in part as a result of dysregulation of the natural immune response. Autoimmune disease is characterized by chronic activation of lymphocytes that recognize and attack naturally occurring, endogenous targets. These chronically activated lymphocytes exhibit a distinct bioenergetic profile in comparison to acutely activated immune cells, which provide a target for therapeutic intervention. Lycera is developing modulators of the mitochondrial ATPase to treat autoimmune conditions such as inflammatory bowel disease (IBD). The talk will include a description of the identification and characterization of Lycera’s current lead candidate for treating IBD.

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

10:30 AKB-4924: Targeting Hypoxia Inducible Factor 1 for Therapy of Inflammatory Bowel Disease

Kevin Peters, M.D., CSO and Senior Vice President, R&D, Aerpio Therapeutics, Inc.

Emerging evidence shows that hypoxia inducible factor 1 (HIF-1) is an important regulator of the immune response. AKB-4924 is a novel small molecule inhibitor of HIF prolylhydroxylases (PHDs), a family of enzymes that promotes HIF degradation. AKB-4924 preferentially stabilizes HIF-1 over HIF-2 and has profound beneficial effects in multiple models of inflammatory bowel disease by either parenteral or oral administration without concomitant increases in erythropoiesis. These data support advancement of AKB-4924 into the clinic.

11:00 CHDI-00340246: A Potent and Selective Kynurenine Monooxygenase Inhibitor as a Potential Therapeutic Agent for the Treatment of Huntington’s Disease

Leticia Toledo-Sherman, Ph.D., Director of Medicinal Chemistry, CHDI Foundation

Deregulation of the kynurenine pathway, has been implicated in the pathophysiology of Huntington’s Disease (HD). This talk will describe CHDI’s medicinal chemistry efforts that lead to the identification of CHDI-00340246, a highly potent and selective KMO inhibitor that has been nominated as clinical candidate for the treatment of HD. We will describe the pharmacokinetic/pharmacodynamics effects of CHDI-00340246 in several species, as well as its biological effects in various disease models.

11:30 Towards Third Generation Antihistamines as Potent Inflammation Inhibitors

Iwan de Esch, Ph.D., Professor, Medicinal Chemistry, VU University Amsterdam & Griffin Discoveries BV

The histamine receptor consists of four subtype GPCRs. The histamine H1 receptor has been successfully targeted by two generations of blockbuster drugs. With the emerging insights into the role of the other histamine receptor subtypes in the different mechanisms of inflammatory responses, there is now a growing interest in poly-pharmacological approaches. We will disclose how fragment-based approaches and computer-aided drug design have resulted in series of compounds with well defined activity profiles for histamine receptor subtypes. These compounds proof potent anti-inflammatory compounds in various preclinical studies.

12:00 pm Close of Track