Protein-Protein Interactions (PPIs) are the basis of many important cellular processes and being able to disrupt or stabilize PPIs offers innovative routes for new therapeutics. However, PPIs are difficult to screen against due to their lack of easily assayable output (no enzymatic activity to measure). Indeed, some pharmaceutical industry companies remain apprehensive of full-fledged drug discovery campaigns in this direction. Yet progress is being made, in large part thanks to advances in biophysical techniques, which enable detection and measurement of interactions between molecules. Rational design of PPI inhibitors based on protein structures and computational analysis has also spurred progress, but figuring out which sites to target in these ‘new’ types of targets has posed a challenge. This meeting gathers leading medicinal chemists, biophysical chemists, structural biologists and discovery biologists in the drug discovery industry to share their successes and failures with the goal of making the pathway for PPI-targeted compounds to therapeutic success less murky. Are there ‘rules’ or commonalities to be gleaned from shared experiences?

Final Agenda

Monday, April 24

7:00 am Registration and Morning Coffee

TARGETING PPIs FOR IMMUNOLOGY AND INFECTIOUS DISEASES

8:00 Chairperson’s Opening Remarks

Laura Silvian, Ph.D., Principal Scientist and Head, Physical Biochemistry, Biogen

8:10 Complement Factor D Inhibitors: Blocking Interactions with Factor B via Fragment-Based Approaches

Fredrik Edfeldt, Ph.D., Associate Principal Scientist, Biophysics, Discovery Sciences, Astra Zeneca R&D

Complement Factor D (CFD) is an atypical self-inhibited Ser-protease that is activated only when binding to Complement Factor B. Our approach has been to block enzymatic activity by targeting and stabilizing the inactive form of CFD. When other hit-finding methods failed, we succeeded using fragment-based approaches. Initially we identified a weak (2 mM) fragment hit by SPR. Structure based design was then used to develop inhibitors with a roughly 20000-fold improvement in affinity from the starting point.

8:40 Using Encoded Library Technologies to Discover Small Molecule Inhibitors of RSV Protein Complexes

Christopher Phelps, Ph.D., Manager, Drug Design & Selection Boston, RD Platform Technology & Science, GSK

Respiratory Syncytial Virus (RSV) remains a significant unmet cause of severe respiratory infections. RSV-N (nucleoprotein) is a critical component of the virus’ replication machinery, encapsulating the viral RNA genome and forming interactions with other viral proteins (P and L) that form the viral replication complex. DNA encoded library technology (ELT) was used to identify a potent inhibitor of the N/P protein/protein interaction capable of blocking viral replication of cells.

9:10In silico Design of mRNAs as Novel Therapeutics, from Bioinformatics to Quantum Mechanics

Michelle Lynn Hall, Ph.D., Senior Scientist, Computational Chemistry, Moderna Therapeutics

Messenger RNA (mRNA) is gaining momentum as an alternative to traditional biologics-based therapeutics. We employ molecular modeling approaches to design novel, synthetic mRNA therapeutics to facilitate their stability as well as desired protein-mRNA interactions for optimal drug product efficacy. In this talk we describe some of these approaches to rational, structure-based design of mRNA therapies.

9:40 Coffee Break

10:05 p53/Rb Reactivation Modulators for HPV-Positive Head and Neck Cancer

Paramjit Arora, Ph.D., Professor, Department of Chemistry, New York University

The incidence of human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) has rapidly increased over the past 30 years, prompting the suggestion that an epidemic may be on the horizon. We are exploring if targeting the E6-p300 interaction is an effective approach to reactivate p53/Rb in HPV-positive HNSCC. Through rational design we have uncovered small molecules inhibitors that reactivate p53 and potentiate the anticancer activity of cis-platinum in HPV-positive HNSCC

10:35 Rational Design of Human Cyclophilin Inhibitors as Pan-Viral Agents

Jean-Francois Guichou, Ph.D., Professor, Structural Biology Department, Center of Structural Biochemistry, University of Montpellier, France

Cyclophilins are peptidyl-prolyl cis/trans isomerases (PPIase) that catalyse the interconversion of the peptide bond at proline residues. Several cyclophilins play a pivotal role in the life cycle of a number of viruses. The existing cyclophilin inhibitors, all derived from cyclosporine A or sanglifehrin A, have several disadvantages. Here we use a fragment-based drug discovery approach using nucleic magnetic resonance, X-ray crystallography and structure-based compound optimization to generate a new family of non-peptidic, small-molecule cyclophilin inhibitors.

11:05 Inhibiting Interaction of IL17A and Its Receptor

Sepideh Afshar, Ph.D., Principal Research Scientist, Department of Protein Engineering, Eli Lilly and Company

 

11:35 Luncheon Presentation: Discovery of Novel Small-Molecule Protein-Protein Interaction Inhibitors using DNA-Encoded Chemical Libraries

Anthony Keefe, Ph.d., Senior Director, Lead Discovery, X-Chem Pharmaceuticals

X-Chem operates a proprietary DNA-encoded chemistry platform that has been successfully applied to a wide range of target classes and therapy areas and numbers over 220 billion compounds. Of the thirty-one programs that we have licensed to collaboration partners approximately one third are for inhibitors of protein-protein interactions. Examples will also be shown in which multiple DNA-encoded library screens are run in parallel and generate data that simultaneously informs upon specificity, affinity and binding sites.

12:20 pm Session Break

BEYOND ACTIVE-SITE BINDING

1:15 Chairperson’s Remarks

Ben Davis, Ph.D., Research Fellow, Biology, Vernalis Research

1:20 Development of Cytotoxic Bicyclic Peptide Drug Conjugates and Applications in Molecular-Targeted Cancer Therapy

Daniel Teufel, Ph.D., Head of Chemistry, Bicycle Therapeutics

The Bicycle platform is presented where linear peptide libraries, genetically encoded in bacteriophage, are post-translationally cyclised with homo-trifunctional organochemical scaffolds, yielding large bicyclic peptide libraries. These constrained peptide libraries have been screened against a range of targets, including receptors, interleukins, enzymes and serine proteases. This presentation describes the identification and development of a novel peptide macrocycle (2.5 kDa) targeting tumour-overexpressed MT1-MMP, and its applications as a cytotoxic drug conjugate in molecular targeted chemotherapy.

1:50 Junctional Epitope Antibodies as Tools for Screening against PPI Targets

Chiara Valenzano, Ph.D., Principal Scientist, Structural Biology, UCB Pharma

The transient interaction between proteins regulates the majority of biological cellular processes. Here we introduce VHH6, a junctional epitope antibody capable of specifically recognizing a neo-epitope when two proteins interact to form a complex. Orthogonal biophysical techniques have been used to prove the “junctional epitope” nature of VHH6, a camelid single domain antibody recognizing the IL-6–gp80 complex. X-ray crystallography, HDX-MS and SPR analysis confirmed that the CDR regions of VHH6 interact simultaneously with IL-6 and gp80, locking the two proteins together.

2:20 hBfl-1/hNOXA Interaction Studies Provide New Insights on the Role of Bfl-1 in Cancer Cell Resistance and for the Design of Novel Anti-cancer Agents

Maurizio Pellecchia, Ph.D., Professor, Biomedical Sciences; Director, Center for Molecular and Translational Medicine, School of Medicine, University of California Riverside

Members of the anti-apoptotic Bcl-2 proteins, including Bcl-2, Mcl-1, and Bfl-1, inhibit apoptosis by selectively binding to conserved a-helical regions of pro-apoptotic proteins such as Bim, and NOXA. Relative roles of these proteins in cancer resistance to apoptosis were based on binding affinities measured with model BH3 peptides and Bcl-2-proteins taken from mouse sequences, which we report here in in part being misleading. Our studies provide a platform onto which design effective Bfl-1 targeting therapeutics.

2:50 Inhibiting Kinases at Their Substrate Recognition Sites: Structure-Activity and Selectivity of Polo Box-Targeted PLK1 Inhibitors

Campbell McInnes, Ph.D., Associate Professor, Drug Discovery and Biomedical Sciences, University of South Carolina

Protein-protein interactions involved in kinase regulation and substrate recognition have significant potential in drug discovery due to their unique features and therefore allow selectivity and potency of inhibition by avoiding the catalytic site. Since these interfaces typically involve shallow clefts and more diffuse interactions, they are more challenging than the ATP binding site. We have developed and validated a general strategy for protein-protein interactions in the development of non-ATP competitive inhibitors of protein kinase oncology targets through the substrate recruitment site.

3:20Selected Oral Poster Presentations

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

4:30 PLENARY KEYNOTE PRESENTATION

PROTACs: Inducing Protein Degradation as a Therapeutic Strategy

Craig M. Crews, Ph.D., Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology; Professor, Chemistry & Pharmacology, Yale University

Enzyme inhibition has proven to be a successful paradigm for pharmaceutical development, however, it has several limitations. As an alternative, for the past 16 years, my lab has focused on developing Proteolysis Targeting Chimera (PROTAC), a new 'controlled proteolysis' technology that overcomes the limitations of the current inhibitor pharmacological paradigm. Based on an “event-driven” paradigm, PROTACs offer a novel, catalytic mechanism to irreversibly inhibit protein function, namely, the intracellular destruction of target proteins.

 

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

6:30 Close of Day

Tuesday, April 25

7:30 am Continental Breakfast Breakout Discussions

APOPTOSIS AND PPI INHIBITORS

8:30 Chairperson’s Remarks

Samantha J. Allen, Ph.D., Senior Scientist, Lead Discovery-Screening,Janssen R&D

8:35 FEATURED PRESENTATION: IAP Antagonists Synergize with Cancer Immunotherapies

Eric LaCasse, Ph.D., Research Scientist, Apoptosis Research Centre, Children’s Hospital of Eastern Ontario

This presentation reviews the current state and future directions for inhibitor-of-apoptosis (IAP) members. These small-molecule IAP antagonists kill tumor cells in conjunction with TNFalpha while also stimulating immune cells. Immune stimulants are able to induce endogenous TNFalpha which synergizes with these IAP antagonists. In addition, these compounds can provide co-stimulatory signals to T-cells which in the presence of immune checkpoint inhibitor biologics allows for a full-fledged immune response against the tumor.

9:05 The Development of Orally Bioavailable Antagonists of Inhibitor of Apoptosis Proteins (IAPs) for the Treatment of Cancer

Lewis Gazzard Ph.D., Senior Scientist, Discovery Chemistry, Genentech, Inc.

Apoptosis is a tightly regulated process critically dependent on the balance between anti- and pro-apoptotic factors. The inhibitor of apoptosis (IAP) proteins block progression into apoptosis, and are upregulated in many cancers to tip this balance in favor of survival, while the endogenous IAP antagonist SMAC acts to promote cell death. The development of small molecule SMAC mimetics and the identification of two orally bioavailable clinical candidates for the treatment of cancer will be described.

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

 

10:30 Discovery of a Potent Inhibitor of an Anti-Apoptotic PPI Target

Ben Davis, Ph.D., Research Fellow, Biology, Vernalis Research

A number of therapeutically important targets involve disrupting interactions between two proteins (“PPI targets”). Disruption of this type of interface was initially regarded as “undruggable”, but a growing body of literature shows that these interactions can be successfully inhibited by small molecule ligands. We will discuss our experiences and successful approaches to identifying ligands and inhibitors of PPI targets.

11:00Ligand-directed Degradation of GSPT1 by a Novel Cereblon Modulator

Philip Chamberlain, Ph.D., Head of Structural and Chemical Biology, Celgene

The drugs Lenalidomide and pomalidomide bind to the protein cereblon and redirect the CRL4-CRBN E3 ubiquitin ligase to cause the degradation of the transcription factors Ikaros and Aiolos. We now present the discovery of a new cereblon modulator which causes the degradation of the translation factor GSPT1. GSPT1 degradation causes potent anti-tumor effects, and is a further example of ligand-directed protein degradation of what may have proven to be an otherwise undruggable target.

11:30 Design, Synthesis and Characterization of Modulators of the Inhibitor of Apoptosis (IAP) Family Proteins

Nicholas D. P. Cosford, Ph.D., Professor, Cancer Metabolism& Signaling Networks Program; Associate Director, Translational Research, Sanford Burnham Prebys Medical Discovery Institute

The inhibitor of apoptosis (IAP) proteins are critical regulators of cellular processes in humans. Compounds that modulate IAPs have potential as therapeutic agents to treat cancer and diseases of the immune system. The systematic rational design and synthesis of monovalent Smac mimetics in different structural classes will be presented. The application of IAP modulators to the treatment of cancer and HIV/AIDs will be discussed.

12:00 pm Close of Conference

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