Cambridge Healthtech Institute’s 12th Annual

Protein-Protein Interactions

Targeting PPIs and Nucleic Acid Complexes for Therapeutic Interventions

April 9-10, 2019

Modulating disease-relevant protein-protein interactions (PPIs) or protein-nucleic acid complexes by chemical agents is a strategy for discovering new compounds with therapeutic potential. However intracellular PPIs are harder to rationally design drugs against or screen in a traditional high-throughput biochemical assay than are traditional intracellular targets such as enzymes. PPIs lack an active site to target. Nevertheless, PPI-targeted drug discovery is moving forward. In fact, the first PPI-targeted drug (against the BCL2 complex) was launched a few years ago for cancer and a few more PPIs are the targets of drug candidates in clinical development. Join your drug discovery peers at Cambridge Healthtech Institute's 12th annual Protein-Protein Interactions conference to discuss innovations and challenges in the field of PPI-directed drug discovery.

Final Agenda

Tuesday, April 9

7:00 am Registration Open and Morning Coffee (20 C/D Foyer)

TARGETING MCL-1 AND BCL-2 COMPLEXES
30 B/C

8:00 Welcome Remarks

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

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

8:10 Enabling Fragment and Structure-Based Discovery for Mcl-1 and Bcl-2

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

Preventing sequestration of pro-apoptotic peptides by Mcl-1 or Bcl-2 induces apoptosis. However, the large hydrophobic cleft and flexibility of structure is a challenge for small molecule discovery. I will describe our work (protein production, fragment screening, biophysical methods) to establish structure and fragment based drug discovery that identified hit series of compounds, some of which were subsequently optimized to clinical candidates for cancer therapy.

8:40 Discovery of AZD5991, a Potent and Selective Macrocyclic Mcl-1 Inhibitor for Treatment of Cancer

Scott Mlynarski, PhD, Senior Scientist, Oncology Chemistry, IMED Biotech Unit, AstraZeneca

Using structure-based drug design, we rationally designed a series of macrocyclic inhibitors of the Mcl-1 protein-protein interaction (PPI). The optimized candidate, AZD5991, is a potent and selective binder of Mcl-1 and leads to protein-complex disruption and caspase induction in Mcl-1 dependent cancer cell lines. In vivo, a single intravenous dose of AZD5991 is capable of inducing robust and durable tumor regressions in sensitive xenograft models.

9:10 NEW: Spotlight Poster Presentations

A4: Drugging the 'Undruggable' Steroid Receptor Coactivators

Jin Wang, Baylor College of Medicine

A7: Structure-Activity Relationship Study of a Cyclic Nrf2 Peptide to Develop Potent Inhibitors of the KEAP1/Nrf2 Protein-Protein Interaction

Paula Ortet, Boston University

A34: Development of Stapled Peptides Targeting NCOA1/STAT6 Protein-Protein Interaction

Yeongju Lee, Pohang University of Science and Technology 

9:40 Networking Coffee Break

10:05 AMG176, a Selective MCL-1 Targeted Drug Candidate

Paul E. Hughes, PhD, Principal Scientist, Oncology Research, Amgen

We will describe the discovery and development of AMG 176 a potent and selective MCL1 inhibitor. We rigorously applied small-molecule conformational restriction to optimize chemical matter culminating in the discovery of AMG 176. MCL1 inhibition rapidly induces apoptosis in subsets of hematological cancer cell lines, tumor xenografts, and primary patient samples. The combination of AMG 176 with venetoclax and standard of care agents is synergistic in multiple model systems highlighting the therapeutic promise of AMG 176 as a single agent and in combination.

10:35 Structure-Based Discovery of Selective and Potent Inhibitors of the BCL2 Family

Andras Kotschy, PhD, Director, Oncology, Servier Research Institute

MCL1 sequesters pro-apoptotic BH3 domain containing members of the BCL2 family, which is exploited by cancer cells to evade cell death and develop resistance. The presentation describes how using a fragment-based approach we developed the clinical candidate S64315 (also named MIK665) that Inhibits these protein-protein interactions. Major hurdles were establishing structural support and understanding its limitations, choosing the appropriate pharmacological tools, and addressing the drug-likeness of our potential candidates.

11:05 Prospective Discovery of Small Molecule Enhancers of Specific E3 Ligase-Substrate Interactions

Kyle Simonetta, Ph.D., Senior Scientist, Lead Discovery, Nurix Therapeutics, Inc.

Mcl1 is targeted for ubiquitylation in a phosphorylation dependent manner by the E3 ligase SCF^Fbw7. Similarly, the oncogenic transcription factor β-catenin is targeted for ubiquitylation in a phosphorylation dependent manner by SCF^βTrCP, an interaction that is frequently disrupted in colorectal cancers. We will present the prospective identification and structure-guided development of ‘molecular glue’ compounds that enhance the interaction between β‑Catenin and SCF^β‑TrCP.  These drug-like small molecules insert into the naturally occurring PPI, with contacts optimized for both the substrate and ligase, stimulating SCF^β‑TrCP to ubiquitinate β‑Catenin. The prospective discovery of such ‘molecular glue’ provides a paradigm for the development of small molecule degraders of difficult-to-target proteins.

11:35 Luncheon Presentation: Evolution of Contract Research Organizations to Contract Innovation Organizations?

Vicky Steadman, PhD, Business Line Leader, Integrated Drug Discovery, Eurofins Discovery (formerly Eurofins Pharma Discovery Services)

CROs were employed by their customer to carry out certain pre-designated tasks. However, CROs evolved to provide solutions to customer’s challenges and are evolving further to provide innovation in the form of project ideas. Collaborative partnerships on integrated drug discovery projects are now common in the drug discovery landscape. Eurofins, an integrated drug discovery provider, will present a successful case history which led to pre-clinical candidates for a pharma partner on a challenging PPI target.

12:20 pm Session Break

PROTEIN-NUCLEIC ACID COMPLEXES AS DRUG TARGETS

1:15 Chairperson’s Remarks

Marianne Sadar, PhD, Professor, Pathology and Genome Sciences, University of British Columbia/BC Cancer Agency

1:20 Targeting RNA: Discovery of Risdiplam; a Selective SMN2 Gene Splicing Modulator for the Treatment of Spinal Muscular Atrophy

Hasane Ratni, PhD, Expert Scientist, Medicinal Chemistry, F. Hoffmann-La Roche, Basel, Switzerland

RNA splice modifiers are a new class of small molecule therapeutics. We have been developing orally available small molecules to increase levels of SMN protein via the alternative splicing of the survival motor neuron 2 (SMN2) pre-mRNA for the treatment of spinal muscular atrophy. We will present the discovery of risdiplam, and its full profile. This compound is currently completing pivotal clinical trials in all type SMA patients.

1:50 Gene Signature Screen (GSS) to Identify Novel Modulators of a Transcriptional Factor

Seong Joo Koo, PhD, Senior Scientist, Lead Discovery, Janssen Pharmaceutica NV

Gene Signature Screening (GSS) is an emerging multiparametric approach to identify disease-associated pathway modulators. We evaluated the potential of GSS to identify novel small molecule inhibitors of a transcription factor by screening 57,000 compounds using a 22-gene signature. Our results show that GSS can identify novel and known inhibitors, demonstrating that GSS can be used to discover inhibitors of transcription factors that are traditionally considered as “undruggable targets.”

2:20 Small-Molecule Covalent TEAD•Yap Antagonists

Samy Meroueh, PhD, Associate Professor, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine

Hippo signaling controls tissue homeostasis and organ growth by regulating Yap co-activation of TEA domain (TEAD) transcription factors. We report small-molecule TEAD•Yap inhibitors that selectively form a covalent bond with a conserved cysteine in the palmitate pocket of TEADs. In mammalian cells, the compounds formed a covalent complex with TEAD4, inhibited its binding to Yap1, blocked its transcriptional activity, suppressed expression of CTGF, and inhibited cell viability of glioblastoma spheroids.

2:50 Novel PPI Inhibitors Targeting the Centrosome to Fight Cancer

Kamyar Hadian, PhD, Group Leader, Helmholtz Zentrum Muenchen

Centrosome amplification is a hallmark of human cancers that can trigger cancer cell invasion. To survive, cancer cells cluster amplified extra centrosomes and achieve pseudo-bipolar division. Here, we set out to prevent clustering of extra centrosomes by identifying novel small molecules that target the Tubulin-CPAP protein-protein-interaction. Biochemical, cell-based and in vivo validation demonstrate a global approach to target various cancers including drug-resistant cancers exhibiting high incidence of centrosome amplification.

3:20 NEW: Allosteric Inhibitor of β-catenin Selectively Targets Oncogenic Wnt Signaling in Colon Cancer

Elmar Nurmemmedov, PhD, Principal Investigator & Director of Drug Discovery, John Wayne Cancer Institute at Providence St. John’s Health

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

4:30 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute

4:35 Plenary Technology Spotlight: Molecular Modelling for the Masses: Orion

Paul Hawkins, Head, Scientific Solutions, OpenEye Scientific

The advent of cloud computing has been transformative for many fields that utilize computation, including drug discovery. The cloud offers robust, elastic, and scalable compute resources through a browser, decreased IT overhead, costs, and time to obtain actionable results. In this presentation I illustrate how the cloud, and in particular OpenEye’s web-based platform Orion, is democratizing molecular modelling by providing easy to use access to cutting-edge molecular design tools coupled with essentially unlimited compute resources.

5:05 Plenary Keynote Introduction

Vicky Steadman, PhD, Business Line Leader, Integrated Drug Discovery, Eurofins Discovery (formerly Eurofins Pharma Discovery Services)

5:10 PLENARY KEYNOTE: Chemical Biology of Proteostasis

Jack Taunton, PhD, Professor, Department of Cellular and Molecular Pharmacology, University of California San Francisco

We have recently discovered several macrocyclic compounds that potently and selectively modulate protein homeostasis. I will discuss our recent efforts to unravel their molecular mechanisms.

6:00 Welcome Reception in the Exhibit Hall with Poster Viewing

7:00 Close of Day

Wednesday, April 10

7:30 am Continental Breakfast Breakout Discussions - View All Breakouts

INNOVATIONS FOR TARGETING OF PPIs

8:30 Chairperson’s Remarks

Samantha J. Allen, PhD, Principal Scientist, Screening, Janssen R&D LLC

8:35 Cereblon Neosubstrate Degradation in Efficacy and Teratogenecity

Philip Chamberlain, DPhil, Senior Director, Structural and Chemical Biology, Celgene

Cereblon modulators are a class of small molecules, including the approved drugs lenalidomide and pomalidomide, that are capable of inducing degradation of target proteins. Cereblon modulators function by scaffolding a protein-protein interaction between cereblon and target proteins resulting in their ubiquitination and proteasomal degradation. A structural understanding has provided a rationale for the mechanism of action, and is enabling the discovery of new substrates and therapeutic mechanisms.

9:05 Discovery and Clinical Development of Drugs Targeting the Intrinsically Disordered Region of Androgen Receptor

Marianne Sadar, PhD, Professor, Pathology and Genome Sciences, University of British Columbia/BC Cancer Agency

Androgen receptor (AR) is a transcription factor and validated therapeutic target for prostate cancer. Resistance to therapies targeting AR is mediated by expression of constitutively active splice variants of AR that lack its ligand-binding domain. Thus targeting the intrinsically disordered N-terminal domain of AR is of interest. We report our approach to the discovery and clinical development of small molecule inhibitors of this drug target previously considered to be “un-druggable.”

9:35 Coffee Break in the Exhibit Hall with Poster Awards Announced

Poster Awards Sponsored by Domainex

FRAGMENT-BASED LIGAND DISCOVERY AND PPIs

10:30 FEATURED PRESENTATION: Molecular Glues for Protein-Protein Interactions: A Fragment-Based Approach to Stabilize 14-3-3/Client Complexes

Michelle Arkin, PhD, Professor, Department of Pharmaceutical Chemistry, University of California San Francisco

Many proteins have multiple binding partners, potentially inducing different biological effects. Stabilizing such protein-protein interactions offers an opportunity to dial in specificity for both partners, and can be inhibitory, activating, or synthetic. Our team is developing specific stabilizers of 14-3-3/client proteins to evaluate the scope and limitations of these effects. This talk will describe our initial foray in the 14-3-3 stabilization using fragment-based drug discovery approaches.

11:00 Biophysics and Structural Biology Offer a Direct Path to Allosteric Drugs

Gregg Siegal, CEO, ZoBio

Allosteric drugs offer exciting new opportunities. ZoBio's platform of biophysics and structural biology allows us to design campaigns that directly seek allosteric modulators of pharmaceutical targets. I will illustrate this capability using HSP70 as an example. HSP70 is a validated target in both oncology and neurodegeneration and yet, has proven challenging to drug. The process used to develop compounds that are selective for the ADP-bound form and inhibit ATPase activity will be described.

11:30 Fragment Philosophy Used in the Identification of eFT508, an Oral, Potent and Highly Selective Inhibitor of Mitogen-Activated Protein Kinase Interacting Kinase (MNK) 1 and 2

Paul Sprengeler, PhD, Research Fellow, Medicinal Chemistry, eFFECTOR Therapeutics, Inc.

Starting from a handful of fragments and fragment-like molecules, the crystal structure-guided approach, leveraging stereoelectronic interactions, to eFT508, an exquisitely selective, potent dual MNK1/2 inhibitor, will be presented. eFT508 was designed to assess the potential for control of oncogene signaling at the level of mRNA translation and has shown potent in vivo anti-tumor activity in models of DLBCL and solid tumors. It is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma.

12:00 pm Close of Conference