Cambridge Healthtech Institute’s 11^th Annual

Protein-Protein Interactions

Targeting PPIs for Therapeutic Interventions

April 3-4, 2018 | Hilton Bayfront | San Diego, California

Protein-Protein Interactions (PPIs) as drug targets commonly refers to the surface of two interacting intracellular proteins or a complex of proteins that can potentially be disrupted or stabilized by a small molecule agent that penetrates the cell. This is in contrast to ‘traditional’ small molecule targets -- enzymatic proteins, whose activity (or loss thereof) can be measured in a biochemical assay. Protein complexes are the basis of many important physiological processes and therefore potential targets for therapeutic compounds. Until recently, intracellular PPIs were considered hard to target because the sites of PPIs are typically flat and large, quite different from the ‘grooves’ or pockets in which small molecules typically bind. Furthermore, a change in conformation or disruption of a complex is harder to measure than loss of enzymatic activity. However, now ‘hotspot’ characteristics on PPIs are being discovered that are more amenable to inhibition by small molecules. In addition, biophysical techniques for measuring protein interactions have become more robust, enabling drug discovery applications. We gather leading medicinal chemists, biophysical chemists, structural biologists and discovery biologists within pharma and academia to share their failures/lessons learned and search for commonalities for this new class of high-drug potential targets.

Final Agenda

Tuesday, April 3

7:00 am Registration and Morning Coffee

ONCOLOGY PPI TARGETS

8:00 Welcome Remarks

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

Kevin Lumb, PhD, Director, Discovery Sciences, Janssen R&D

8:10 Enabling Fragment and Structure-Based Discovery for Challenging Targets (Bcl-2, Mcl-1)

Roderick E. Hubbard, PhD, Professor, University of York and Director, Vernalis

Working on unprecedented targets is tough. It can take some time to generate suitable protein, develop an assay that can be trusted, identify tool compounds and design optimised molecules in the absence of structural information. I will describe our approaches to establish fragment and structure-based discovery for such targets, using as examples the early work on Bcl-2 and Mcl-1 with Servier that resulted in compounds that are now in Phase I clinical trials.

8:40 Structure-Based Design of Novel Inhibitors of the MCL-1’s Protein-Protein Interaction

Xin Huang, PhD, Principal Scientist, Department of Molecular Engineering, Amgen

Mcl-1, a member of the Bcl-2 family, inhibits pro-death components of the intrinsic apoptosis pathway and thus is a key survival factor in multiple myeloma and other malignancies. Although compelling, targeting disruption of Mcl-1’s protein–protein interaction to induce tumor cell death was previously thought to be “un-druggable” due to the high affinities of Mcl-1 to the pro-apoptotic Bcl-2 proteins and lack of a small molecule binding pocket. We report here our structure-based drug design of novel inhibitors of the Mcl-1 that led to AMG 176, a potent, selective, and bioavailable Mcl1 inhibitor in clinical development.

9:10 Screening for Conformational Changes using Second Harmonic Generation (SHG)

Artem Evdokimov, PhD, CSO, HarkerBIO

9:40 Coffee Break

10:05 Discovery of Potent and Selective Mcl-1 Inhibitors Using Fragment Merging and Structure-Guided Design

James (Chris) Tarr, PhD, Drug Discovery Scientist II, Stephen Fesik Laboratory, Department of Biochemistry, Vanderbilt University

Mcl-1 is a member of the Bcl-2 family of proteins responsible for the regulation of apoptosis and a highly validated target for cancer therapy. Using fragment screening by NMR followed by lead optimization employing structure-based design methods, we have developed selective, picomolar inhibitors of Mcl-1. These compounds act via the intrinsic apoptotic pathway, potently inhibit proliferation in cellular assays, and deliver efficacy in xenograft tumor models. Efforts to develop a suitable clinical candidate are underway.

10:35 Targeting Nuclear Lamins to Inhibit DNA Repair

Xiangshu Xiao, PhD, Associate Professor, Physiology and Pharmacology, Oregon Health & Science University

Targeting DNA repair pathways has been validated as a promising strategy to develop novel cancer therapeutics. However, it has been very challenging to target DNA repair proteins. We have discovered a novel role of lamins in DNA repair and have developed the first-in-class small molecules to target lamins to inhibit DNA repair. We will present our exciting discovery in this space.

11:05 Computational Screening for Small Molecule Protein-Protein Interaction Inhibitors

Samy Meroueh, PhD, Associate Professor, Department of Biochemistry and Molecular Biology, Indiana School of Medicine
Tight protein-protein interactions pose a unique challenge to the use of structure-based computational screening of large chemical libraries to identify small-molecule inhibitors. Here, we explore mimicry of the pairwise intermolecular interactions between critical residues as a strategy to enrich commercial libraries. We introduce three methods that use critical residues of the receptor, the ligand, or a combination of the two. We apply these methods to the tight uPAR•uPA interaction, and we report the work that identified some hits as lacking stability, thiol reactive, or redox active.

11:35 Luncheon Presentation: The Rational Design of Small-Molecule Neuropilin-1 Antagonists

Trevor Perrior, PhD, Chief Scientific Officer, Domainex

Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor A165 (VEGF-A) and the neuronal guidance molecule semaphorin 3A (SEMA3A), which plays a key role in vascular and neuronal development. Molecules which antagonise the interaction of NRP-1 with its protein ligands may be useful in a number of therapeutic settings, in particular for the treatment of certain types of cancer. In collaboration with Ark Therapeutics and scientists at University College London we have designed the first small-molecule inhibitors of this protein-protein interaction and have shown that they display the expected pharmacological profile.

12:20 pm Session Break

TARGETING VIRAL, NEURODEGENERATION AND OTHER PROTEIN COMPLEXES

1:15 Chairperson’s Remarks

Roderick E. Hubbard, PhD, Professor, University of York and Director, Vernalis

1:20 HBV Capsid Assembly Inhibitors

Andrew Cole, PhD, Research Fellow, Medicinal Chemistry, Arbutus

The encapsidation of pregenomic RNA by dimeric units of hepatitis B virus core protein is an essential step in the viral life cycle of HBV, facilitating viral genome relaxed circular DNA synthesis, infectious virion production and maintenance of a nuclear covalently closed circular DNA pool. Small molecules that bind at the core protein dimer:dimer interface have been shown to demonstrate antiviral activity in vitro and in vivo, through interference with the HBV capsid assembly process.

1:50 FEATURED PRESENTATION: Assessing Mitochondrial Quality Control to Inform Discovery of Small Molecules Targeting the Keap1-NRF2 System

Michelangelo Campanella, PhD, PharmD, Professor and Unit Head, Mitochondrial Cell Biology and Pharmacology Research Group RVC and University College London Consortium for Mitochondrial Research
My talk will report upon Nrf2 inducers as pharmacological tolls in mitochondrial quality control operated by targeted autophagy. It will elaborate on the prominent biological activity in cellular homeostasis of the non-covalent Keap1-Nrf2 protein-protein interaction (PPI) inhibitor PMI, which is structurally distinct from the covalent Keap1 modifiers (e.g. sulforaphane) and amenable to therapeutic exploitation. Contextually, a newly devised method for High Throughput Screening (HTS) for this specific category of Keap1-Nrf2 inhibitors will be presented.

2:20 Thermodynamics-driven Structure-Activity Relationship Studies: Breaking the Enthalpy-Entropy Compensation Saga Results in Novel and Potent IAP and XIAP Antagonists

Maurizio Pellecchia, PhD, Professor of Biomedical Sciences, University of California, Riverside (UCR) School of Medicine

Using NMR and thermodynamic screening approaches with focused positional scanning libraries (fPOS) novel areas on the target surface can be identified that can be further exploited to design more potent and selective ligands. I will report on our recent work targeting the BIR3 domains of IAP family proteins, and will illustrate that enthalpy-entropy compensation in thermodynamics-driven structure activity relationships studies can be used to design both novel pan-active agents and novel XIAP selective compounds.

2:50 Drug Leads Originating from the Public/Private Consortium: European Lead Factory

Dimitrios Tzalis, PhD, CEO, Taros Chemicals; Head of Chemistry, European Lead Factory

Highlights of the European Lead Factory (ELF)

• a public-private partnership that provides researchers in Europe a unique platform for translating innovative biology and chemistry into high-quality starting points for drug discovery
• 200.000 de novo synthesized compounds are complimenting 300.000 compounds provided by participating pharmaceutical partners
• So far resulted in >5.000 hit compounds with a defined biological activity from >90 successfully completed HTS and hit evaluation campaigns out of which a significant number of targets are PPIs

3:20 Selected Poster Presentations

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

4:30 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

4:35 Sponsored Plenary Keynote Introduction (Opportunity Available)

4:40 PLENARY KEYNOTE: Activity-Based Proteomics: Protein and Ligand Discovery on a Global Scale

Benjamin F. Cravatt, PhD, Professor and Co-Chair, Department of Molecular Medicine, The Scripps Research Institute
To address uncharacterized proteins, we have introduced chemical proteomic technologies that globally profile the functional state of proteins in native biological systems. Among these methods is activity-based protein profiling (ABPP), which utilizes chemical probes to map activity states of large numbers of proteins in parallel. I will discuss the application of ABPP to discover and functionally annotate proteins in mammalian physiology and disease, and the generation and implementation of advanced ABPP platforms for proteome-wide ligand discovery.

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

6:30 End of Day

Wednesday, April 4

7:30 am Continental Breakfast Breakout Discussions

CANCER, EPIGENETICS AND PPIs

8:30 Chairperson’s Remarks

Chris Smith, PhD, Director, Medicinal Chemistry, COI Pharmaceuticals

8:35 Design of Allosteric K-Ras Inhibitors Targeting the Switch II Pocket

Juan J. Perez, PhD, Professor, Department of Chemical Engineering, Universitat Politecnica de Catalunya, Barcelona

K-Ras is an oncoprotein involved in numerous cancers. Inhibition of K-Ras has been elusive for many years because it cannot be competitive, due to the high affinity of the protein for GTP. Recently, small molecule inhibitors targeting the G12C K-Ras mutant have been disclosed. These molecules produce their action binding irreversibly into the inducible switch II pocket. In the present communication, we describe a novel series of reversible switch II inhibitors with nanomolar affinity.

9:05 NuRD Epigenetic Complex: An Emerging Target for Cancer Chemo-Sensitization

Elmar Nurmemmedov, PhD, MBA, Assistant Professor, Director of Drug Discovery, Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute

NuRD complex plays a major role in the regulation of gene expression, chromatin organization, DNA damage repair, and genomic stability. NuRD complex is also involved in acquired resistance to chemotherapies in a number of cancers, including deadly brain cancers. Targeting RBBP4, an integral component of this complex, sensitizes resistant cancer cells to chemotherapy. We developed an approach that enables inhibition of RBBP4 and leads to selective elimination of resistant cancer cells; this is a new direction in targeting of chemo-resistant cancer cells.

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

FRAGMENT-BASED APPROACHES TO FIND PPI INHIBITORS

10:30 Fragment-Based Discovery of a Chemical Probe for the NSD3-PWWP-1 Domain

Jark Böttcher, Principal Scientist, Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co KG

We describe the fragment-based discovery of molecules binding to the proposed methyl-lysine binding site of the PWWP-1 domain of NSD3. Supported by a virtual screening approach and subsequent structure-based optimization, the initial hits were optimized into a chemical probe with confirmed binding in cellular assays. The probe and the related negative control can be used to explore the functions of the PWWP-1 domain.

11:00 Lead Generation without an X-Ray Crystal Structure: An NMR Method to Probe Protein-Ligand Complexes

Julien Orts, PhD, Professor, Laboratory of Physical Chemistry, Swiss Federal Institute of Technology ETH

My talk is about a NMR method to solve protein-ligand complex structure. I will present two or three examples of this method applied to finding inhibitors against specific PPI targets.

11:30 In silico Fragment Screening to Identify Cryptic Pockets and Allosteric Sites for PPI Inhibitor Development

Ben Cossins, PhD, Principal Scientist, UCB Pharma

Drug development is increasingly difficult and expensive. Valuable targets are not always amenable to modulation by small molecules and resources are often directed towards seemingly intractable targets. We have been building and applying molecular dynamics based fragment screening and de novo design approaches to try and understand ligandability and functionability for protein-protein interaction targets. We believe this approach can steer us towards hit compounds for tractable PPI targets.

12:00 pm End of Conference