Cambridge Healthtech Institute’s 8th Annual

Macrocyclics & Constrained Peptides

Discovery and Design of Cell-Penetrating, Middle-Sized Molecules for Oral-Based Medicines

April 14-15, 2020

In the drug discovery industry, synthetic macrocyclic compounds theoretically fit the bill for new chemical entities that have good drug potential yet can access newer drug targets such as protein-protein interactions (PPIs) that are intracellular and more complex than traditional enzymatic targets. Indeed, there are examples of naturally occurring macrocyclics, such as cyclosporin, that have become successful drug compounds. Synthetic macrocyclics' 'idealness' however is still being optimized. Please join us to stay abreast and discuss challenges that remain in the discovery, design and optimization of macrocyclic compounds or constrained peptides with good oral bioavailability and cell penetration.

Final Agenda

Day 1 | Day 2

Tuesday, April 14

7:00 am Registration Open and Morning Coffee

NEW APPROACHES FOR CONSTRUCTING MACROCYCLIC SCAFFOLDS

8:00 Welcome Remarks

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

8:05 Chairperson’s Opening Remarks

Christian Cunningham, PhD, Scientist, Early Discovery Biochemistry, Genentech

8:10 Macrocycles to Control Peptide Conformation and Activity

Paramjit Arora, PhD, Professor, Chemistry, New York University

We are pursuing a systematic approach to develop synthetic inhibitors of PPIs. Proteins often utilize small folded domains for recognition of other biomolecules. The basic hypothesis guiding our research is that by mimicking these domains, we can modulate the function of a particular protein with metabolically stable synthetic molecules. This presentation will discuss covalent constraints to stabilize protein domain mimics (PDMs) in isolated sequences.

8:40 Encoded Macrocyclic Peptide Libraries in Drug Discovery

Christoph Dumelin, PhD, Laboratory Head and Project Leader, Chemical Biology & Therapeutics, Novartis Institutes for Biomedical Research

The pharmaceutical industry is continuously expanding into unchartered territory in terms of both target space and therapeutic modalities. The identification of suitable chemical matter suitable enabling such projects using the libraries and screening technologies developed over the last decades has turned out to be challenging. This talk will give an overview of how we apply our encoded macrocyclic peptide library platform to tackle these challenges.

9:10 Oncodesign's Integrated Drug Discovery Services for Developing New Drug Candidates and Cyclic Inhibitors

Alexis Denis, PhD, Director, Discovery Medicinal Chemistry, Oncodesign

Oncodesign’s Integrated Drug Discovery Services combine pharma drug discovery expertise, from hits finding to preclinical candidates, across platforms: medicinal chemistry, pharmacology, pharmaco-imaging & DMPK, for the fast development of new drug candidates. Our medicinal chemistry expertise also covers the macrocyclization of small Lead-like which is the core of our kinase drug discovery programs. We will present some examples of current ongoing programs using either the optimization of preformed macrocycle or fragments to macrocycle approach.

9:40 Networking Coffee Break

10:05 Syrbactin Proteasome Inhibitors for Oncology and Immune Disorders

Michael Pirrung, PhD, Distinguished Professor of Chemistry, University of California Riverside

Drug candidates based on the syrbactins, macrocyclic peptide natural products, are being developed for autoimmune disorders and bortezomib-resistant multiple myeloma. They show irreversible, covalent proteasome modification, high specificity for particular proteasome catalytic subunits in cell culture, no off-targets in adverse drug reaction screens, and a good therapeutic index in animal models. We exploit the syrbactin macrocycle to predict, analyze, and control the 3D conformations of our drug candidates, which affect their proteasome selectivity.

10:35 Targeting NRF/Keap1 with a Cyclic Peptide

Adrian Whitty, PhD, Associate Professor, Department of Chemistry and Department of Pharmacology and Applied Therapeutics, Boston University

The protein-protein interaction of KEAP1 with Nrf2 is a target of high current interest that, due to the highly charged nature of the interface, poses special problems for inhibitor discovery. I will describe progress toward developing a cyclic peptide inhibitor of KEAP1, with emphasis on how we approached optimizing ring size, eliminating strain, occupying binding energy hot spots, and eliminating charged groups that hinder cell permeability.

11:05 Passively Permeable Macrocycles: Inspiration from Nature and the Translation to the Bench

Cameron Pye, PhD, CEO and Co-Founder, Unnatural Products

We’ve been using passively permeable macrocycles found in nature as therapeutics for decades. However, designing this property into synthetic cyclic peptides has proved to be challenging despite the myriad of screening and selection platforms available. This talk will explore how we leverage our platform to turn impermeable binders into passively permeable leads. 

11:35 Session Break

11:45 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:30 pm Session Break

CONSTRAINED PEPTIDES

1:15 Chairperson’s Remarks

J. Jean Cui, PhD, CSO, Turning Point Therapeutics, Inc.

1:20 Cyclotides as Scaffolds for Intracellular Targets

David Craik, PhD, ARC Laureate Fellow – Group Leader, Institute for Molecular Bioscience, Queensland University, Australia

Cyclotides are ultra-stable peptides that are able to penetrate cells. This presentation will describe their membrane interactions and cell-penetrating ability, along with their ability to be loaded with epitopes for intracellular targets.

1:50 A Constrained Peptide for an E3 Ligase

Laura Itzhaki, PhD, Professor, Pharmacology, University of Cambridge

E3 ligases are key regulators of the cell cycle and cell proliferation and important therapeutic targets. The proteins from which they are derived adopt extended, non-helical bioactive conformations, presenting challenges for the rational design of chemical constraints. I will present our work on peptides designed to inhibit two E3 ligases. I will also discuss how we are exploiting our findings and methodologies for targeted protein degradation.

2:20 Constrained Peptides for Drug Discovery

Rami Hannoush, PhD, Principal Scientist, Group Leader, Early Discovery Biochemistry, Genentech

2:50 Elucidating Quality Control at the Ribosome with the Natural Product, Ternatin

Keely Oltion, Graduate Student, Chemistry and Chemical Biology, Laboratory of Jack Taunton, University of California San Francisco

Natural products often provide novel insights into biological processes. We discovered that ternatin, a cyclic peptide natural product, inhibits translation elongation by trapping the elongation factor, EF1A, at the ribosome. Ternatin, but not didemnin B, a structurally unrelated natural product with the same binding site, causes degradation of EF1A. I will describe work towards the mechanism for ternatin-induced EF1A degradation, which may represent a novel form of ribosome quality control.

3:20 Sponsored Presentation (Opportunity Available)

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

4:35 Plenary Welcome Remarks from Event Director with Poster Finalists Announced

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

4:45 Plenary Technology Spotlight: Accelerating Drug Discovery from Hit Finding to Candidate Selection with Physics and Machine Learning-Based Calculations

Matt Repasky, PhD, Vice President, Life Sciences Products, Schrödinger

The impact of the Schödinger computational platform in drug discovery is illustrated using recent case studies from internal and collaborative discovery projects.  The Platform facilitates halving the number of synthesized molecules and time to candidate relative to industry standards.  Key elements of the Platform are described including Free Energy Perturbation to accurately predict relative protein-ligand binding, machine learning to generate and rapidly assess millions of ideas, and collaborative sharing of project information through LiveDesign.

5:10 Plenary Keynote Introduction (Sponsorship Opportunity Available)

5:15 PLENARY KEYNOTE:

Medicinal Chemistry: Where Are We Headed?

Wendy Young, PhD, Senior Vice President, Small Molecule Discovery, Genentech

Major shifts in the way medicinal chemists discover novel medicines have evolved over the past few decades. Technological advances have significantly increased the ability to triage compound design and synthesize compounds faster. New approaches in structural biology have enhanced our ability to visualize molecules and their corresponding binding sites. Drug discovery teams have moved from local to global and our deepened understanding of biology has extended our reach. This lecture will explore past trends in drug discovery, current status of the industry, and the future of medicinal chemistry.

6:00 Welcome Reception in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

7:00 Close of Day

Day 1 | Day 2

Wednesday, April 15

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

MACROCYCLIC-BASED DRUG LEADS

8:30 Chairperson’s Remarks

Scott Lokey, PhD, Professor, Chemistry and Biochemistry, University of California, Santa Cruz

8:35 FEATURED PRESENTATION: Identification of Novel Macrocyclic Bactericidal Inhibitors Targeting the Essential Bacterial ABC transporter MsbA

Christian Cunningham, PhD, Scientist, Early Discovery Biochemistry, Genentech

We detail the use of mRNA display technologies and a unique selection and protein engineering strategy to discover potent macrocycle-based inhibitors of MsbA, an essential bacterial ABC transporter for LPS. A high-resolution cryo-electron microscopy structure reveals the molecular basis for state-dependent inhibition of MsbA. Unexpectedly, peripherally-bound LPS molecules are also observed, expanding our understanding of the mechanisms of substrate transport.

9:05 Type IV Macrocyclic Inhibitors of BRAF Kinase Block Paradoxical Signaling in Resistant Melanomas

Campbell McInnes, PhD, Professor, Drug Discovery and Biomedical Sciences, University of South Carolina

We describe the proof of concept for macrocyclic peptides that inhibit BRAF through binding to the dimerization interface of the RAF kinases. Furthermore, we applied the REPLACE strategy to identify and optimize the peptides for BRAF affinity and increased drug-likeness. The compounds block paradoxical signaling resulting from aberrant activation of BRAF by ATP competitive drugs and thus, have potential as next-generation BRAF inhibitors for treating resistant melanomas.

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

Poster Awards Sponsored by Enamine Ltd

10:30 A Macrocyclic Inhibitor of PDL1

Paul Scola, PhD, Senior Scientist, Medicinal Chemistry, Bristol-Myers Squibb

11:00 Design and Development of Repotrectinib, a Next Generation Macrocyclic ROS1/TRK/ALK Inhibitor

J. Jean Cui, PhD, CSO, Turning Point Therapeutics, Inc.

Drug-resistance mutations have emerged as a major challenge to targeted therapies. Repotrectinib was designed with a novel macrocycle having a much smaller size (MW 355) than current ROS1/TRK/ALK inhibitors and located at the center of the highly conserved ATP site without direct contact with clinical resistance mutations. Repotrectinib potently inhibited both wild type and many mutant ROS1/TRK/ALK. Repotrectinib was well tolerated and demonstrated encouraging overall clinical activity in patients with ROS1 fusion-positive NSCLC and TRK fusion-positive solid tumors.

11:30 Presentation to be Announced

Sepideh Afshar, PhD, Principal Research Scientist, Department of Protein Engineering, Eli Lilly & Company

12:00 pm Close of Conference

12:45 Dessert Break in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

Day 1 | Day 2

* The program is subject to change without notice, due to unforeseen reason.