Original Agenda
We are actively working with our speakers to confirm their availability for the virtual event. Initial response from our speakers has been very positive, and we are optimistic we will have the new programs ready to share here soon.

Macrocyclics and Constrained Peptides, August 25-26 2020, San Diego, CA

Cambridge Healthtech Institute’s 8th Annual

Macrocyclics & Constrained Peptides

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

NEW DATES - AUGUST 25-26, 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

Tuesday, AUGUST 25

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 AroraParamjit 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 DumelinChristoph 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 InhibitorsONCO-design-Biotechnology

Alexis DenisAlexis 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 PirrungMichael 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 WhittyAdrian 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 PyeCameron 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 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 Sponsored Presentation (Opportunity Available)

5:10 Plenary Keynote Introduction (Sponsorship Opportunity Available)


5:15 PLENARY KEYNOTE:

Scott Lockey

Discovery of Bioactive, Passively Permeable Cyclic Peptides: Translating Theory into Practice

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

Cyclic peptides have undergone a renaissance in medicinal chemistry. More and more cyclic peptides are being discovered with surprisingly high passive permeabilities and, in some cases, small molecule-like oral bioavailability. Can we harness that understanding to generate molecules that are both membrane permeable and capable of inhibiting a given therapeutic target? I will describe our latest efforts to predict and control properties in this interesting class of molecules.

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

7:00 Close of Day

Wednesday, aUGUST 26

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

In this session, attendees fill their plate from the breakfast buffet and then 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.

Topic: Lead ID Using Macrocycle Libraries

Moderator: Adrian Whitty, PhD, Associate Professor of Chemistry, Boston University

  • What properties define a good macrocycle screening hit?
  • What represents good potency, and does this depend on library chemistry?
  • Specialized/biased versus general purpose libraries

Topic: Technologies Driving Macrocycle Innovation

Moderator: Cameron Pye, PhD, CEO & Co-Founder, Unnatural Products

  • Hit-finding strategies: DELs, mRNA display, phage, next-gen OBOC, biosynthesis. Where do they work, where do they struggle?
  • Early prioritization: modeling or empirical property-based selection?
  • What is missing? What technologies could rapidly enhance macrocycle discovery and development? Better modeling, more efficient synthesis, more diverse hits...?

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 McInnesCampbell 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 Engineered Cyclotides with Potent Broad Anti-microbial Activity

Julio Camarero, PhD, Professor, Pharmaceutical Sciences, University of Southern California 

The search for novel antimicrobial agents is intensifying, in response to both the threat of microbial pathogens in bioterrorism and the increasing development of drug resistance to current antibiotics. We will present work of the development of novel cyclotides with a good pharmacokinetic profile and effective broad-spectrum antibacterial activity against several ESKAPE bacterial strains. The most active cyclotide showed good activity in vivo using a P. aeruginosa peritonitis animal model.

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

J. Jean CuiJ. 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 Discovery of Synthetic Macromolecules as High Affinity Reagents by Mega - HTS using Fiber Optic Array Scanning Technology (FAST)

Michal Avital-Shmilovici, PhD, Research Scientist, Drug Discovery, SRI International

FAST is capable of screening ~5M assay points in 1 minute. We have used this to design and screen large libraries (107 – 108) of synthetic non-natural polymer macromolecules to routinely find nanomolar to sub-nanomolar binders to ‘undruggable’ targets, such as K-Ras and asialoglycoprotein receptor. With remarkable biological stability and extended in vivo PK half-life, these represent early examples of a new class of synthetic macromolecular modality for therapeutics discovery.

12:00 pm Close of Conference

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