Cambridge Healthtech Institute’s 7th Annual

Macrocyclics & Constrained Peptides

Cell-Penetrating, Bigger Molecules for Oral-Based Therapeutics

April 10-11, 2019

Synthetic macrocyclics and constrained peptides are of growing interest in the pharmaceutical industry because they are expanding the chemical space that can be explored for new therapies. This new class is considered ‘ideal’ because its medium size and ring structure are supposed to combine the best properties of biologics and small molecules. They are small enough to get in cells but large enough for specific interactions with more targets such as protein-protein interactions (PPIs) and their cyclic nature enhances their solubility. Some compounds are advancing in clinical trials. However, challenges still remain such as solubility and cell-penetration. Medicinal chemists continue to refine design ideas. Directed-evolution approaches to create libraries based on macrocyclics are also being applied. Join us at Cambridge Healthtech Institute's 7th Annual Macrocyclics & Constrained Peptides conference to stay abreast of progress and be part of the ground-laying efforts in this new field.

Final Agenda

Wednesday, April 10

12:30 pm Registration Open

12:45 Dessert Break in the Exhibit Hall with Poster Viewing


1:30 Welcome Remarks

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

1:35 Chairperson’s Opening Remarks

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

1:40 FEATURED PRESENTATION: Molecular Chameleons: Oral Compounds at the Border of Druggable Chemical Space

Jan Kihlberg, PhD, Professor, Department of Organic Chemistry, Uppsala University

Our analyses of crystal and solution phase structures of compounds at the border of oral druggable space suggest that they must behave as molecular chameleons. Depending on the environment they populate, small and distinct sets of conformations allow them to combine aqueous solubility with cell permeability and potent target binding. Predicting the conformations and properties of molecular chameleons is difficult, but our studies allow us to speculate on what future breakthroughs might be.

2:10 Advances in the Synthesis and Applications of Macrocycles

Andrei K. Yudin, PhD, Professor, Department of Chemistry, University of Toronto

Synthetic tools that allow one not only to cyclize linear precursors but also to exercise control over conformation-driven cellular permeability are in high demand. This lecture will summarize our ongoing efforts in this area and will highlight key experimental findings obtained in the past few months.

2:40 The Permeability Landscape around Lariat Cyclic Peptides

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

Heterodetic cyclic peptides (lariat peptides) differ from simple homodetic cyclic peptides by the addition of a tail extending from the cyclic portion. Although lariat peptides comprise a large portion of bioactive cyclic peptide natural products, exploration of permeability in this space has been limited. We recently discovered a simple lariat scaffold based on a natural product, Xentrivalpeptide A, composed entirely of non-N-methylated alpha amino acids. I describe the synthesis and properties of several passively permeable lariat peptides with six H-bond donors and molecular weights greater than 800.

3:10 Presentation to be Announced

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Versatile Bio-Orthogonal Strategies for Synthetic Peptide and Protein Stabilization

Raymond E. Moellering, PhD, Assistant Professor, Department of Chemistry, Institute for Genomics and Systems Biology, University of Chicago

Numerous chemistries have been applied to stabilize specific peptide conformations. Many of these strategies, however, lack the general structural, chemical and environmental compatibility desirable for diverse applications in enforcing bioactive peptide and protein folds. In this talk I will present recent progress on the development and application of novel chemical strategies to stabilize secondary and tertiary peptide conformations for challenging pharmacologic targets.

5:00 A*STAR Peptide Engineering Platform (PEP): Targeting Macrocyclic Modalities for Protein-Protein Interactions

Charlie Johannes, PhD, Principal Scientist II & Head Director, Organic Chemistry, A*STAR

This talk will focus on how A*STAR has embraced the revitalization of peptide research and is evolving technologies to enable the discovery and development of new peptide modalities for protein-protein interactions. Examples targeting the p53 and translational initiation (EIF4F) pathways for oncology and multimodal biomarkers for immunology will highlight our recent advances in diversity, screening, design, chemistry and formulation.

5:30 Breakout Discussions - View All Breakouts

In these sessions, attendees 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: Macrocyclic Lead Optimization

Moderators: Petr Jansa, PhD, Senior Research Scientist II, Medicinal Chemistry, Gilead Sciences

Vicky Steadman, PhD, Director, Discovery, Eurofins Pharma Discovery Sciences

  • Challenging ADME properties
  • Drug design challenges (conformational sampling of macrocycles,IMHB incorporation...)
  • Advances in macrocyclization strategies
  • Natural products as starting points

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

6:15 Close of Day

6:30 Dinner Short Courses*

*Premium or separate registration required.

Thursday, April 11

8:00 am Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee

8:45 Welcome Remarks from Lead Conference Director

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

8:50 Plenary Keynote Introduction

8:55 Plenary Keynote: New Ways of Targeting K-Ras

Frank McCormick, PhD, Professor, HDF Comprehensive Cancer Center, University of California San Francisco

Efforts to find drugs that bind K-Ras directly have increased recently, enabled by NMR-based fragment screening, di-sulfide tethering, in silico drug design and biophysical methods such as Second Harmonic Generation (SHG). We will report progress on attacking two sites in the K-Ras protein; cysteine-185 (the site of prenylation), and histidine-95, a residue unique to K-Ras, to develop covalent K-Ras inhibitors, as well as compounds identified by SHG and other methods.

9:45 Coffee Break in the Exhibit Hall with Poster Viewing


10:40 Chairperson’s Remarks

Adrian Whitty, PhD, Professor, Biochemistry, Boston University

10:45 Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle

Petr Jansa, PhD, Senior Research Scientist II, Medicinal Chemistry, Gilead Sciences

Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties.

11:15 FEATURED PRESENTATION: Third Wave of Macrocyclic Peptide Therapeutics: Benchmarking and Druggable Target Space

Tomi K. Sawyer, PhD, Distinguished Scientist, Peptide Drug Discovery & Innovative Technologies, Merck & Co., Inc.

There have been three major waves of peptide drug discovery –– the first for receptor and extracellular targets, the second for intracellular targets, and now a third that is converging super-diversity (e.g., 106-1012-membered libraries) with both structure-based design and expanding target space. This has inspired new peptide modalities and opportunities to expand drugable target space (e.g., intracellular protein-protein and protein-DNA/RNA interactions). This presentation will highlight progress in the development of new screening tools for peptide permeability for benchmarking macrocyclic α-helical peptide structure-permeability relationships to advance this peptide modality into the clinic.

11:45 Sponsored Presentation (Opportunity Available)

12:00 pm Discovery to Approval: Medicinal Chemistry Retrospective of Lorlatinib, A Macrocyclic ALK Inhibitor for Metastatic and Resistance Non-Small Cell Lung Cancer

Ted. W. Johnson, PhD, Research Fellow, Design Chemistry, Pfizer Oncology

PF-06463922 (lorlatinib), a novel macrocyclic inhibitor of ALK/ROS1, recently received FDA approval for the treatment of ALK-refractory Non-Small Cell Lung Cancer. Lorlatinib exhibits low nanomolar, cell-based inhibitory activity against a panel of clinically-derived ALK kinase-domain mutations and overlapping CNS activity to treat brain metastases. A complete retrospective will be presented with focus on unique lab objective and safety challenges.

Schrodinger12:30 Luncheon Presentation to be Announced

1:30 Dessert Break in the Exhibit Hall with Poster Awards Announced

Poster Awards Sponsored by Domainex


2:15 Chairperson’s Remarks

Lauren Monovich, PhD, Director, Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Inc.

2:20 Cell-Penetrating Mini-Proteins against B-Catenins

Milenko Cicmil, PhD, Vice President, Translational Biology, FOG Pharma

2:50 Macrocyclic Agonists of the Neurotensin Receptors: Tools to Modulate Receptor Selectivity and Undesired Effects

Eric Marsault, PhD, Professor, Medicinal Chemistry and Pharmacology, University of Sherbrooke

The 13- amino acid peptide neurotensin is the endogenous ligand of the NTS1 and NTS2 receptors. Activation of the neurotensin receptors leads to opioid-independent analgesia yet is associated with hypothermia and hypotension. Based on the C-terminal portion of neurotensin, we implemented macrocyclization with the goal to fine-tune receptor selectivity and increase ligand stability.

3:20 Macrocycles Targeting Intracellular PPIs for Addressing Refractory Oncology Targets

David Spellmeyer, PhD, CSO, Circle Pharma

Circle Pharma deploys a structure–based design/synthetic chemistry platform for macrocycle therapeutic discovery that incorporates prediction of intrinsic cell permeability as a key step in the design workflow. While this platform is target-agnostic, Circle’s internal pipeline is directed to intracellular protein-protein interactions that are key drivers in oncology pathways, including p53:MDM2/4, MCL1:BH3, cyclinA:cdk2 and beta-catenin:TCF4. Examples of Circle’s development work will be presented.

3:50 Networking Refreshment Break

4:20 Macrocyclic Peptide Triazole Inhibitors as Irreversible HIV-1 Inactivators

Adel Ahmed, PhD, Research Assistant Professor, Biochemistry and Molecular Biology, Drexel University College of Medicine

Through a facile chemical synthesis pathway based on solid phase peptide synthesis, we have developed a class of small cyclic peptides (cPTs) that target the HIV-1 Env gp120 glycoproteins. cPTs have great lipophilicity/hydrophilicity balance and have good aqueous solubility, making them appealing to develop as an orally bioavailable therapeutic. cPTs also have promising pharmacokinetics (PK) in rats with an estimated half-life of > 3 hours. They resist proteolysis by model and serum proteases.

4:50 New Cyclic Peptidomimetics to Combat Bacterial Infections

Brice Felden, PhD, Professor, Bacterial Regulatory RNAs & Medicine, Rennes University

This presentation will describe novel therapies we are developing against Gram positive and negative bacteria. They are based on cyclic peptidomimetics. These new modalities do not trigger resistance in vivo.

5:20 Hydrocarbon-stapled Peptidomimetics Targeting Relaxin-3/RXFP3 Networks in Eating and CNS Disorders

Subhi Marwari, PhD, Postdoctoral Research Associate, Department of Medicine and Neuroscience, SUNY Upstate Medical University

The “helix-in-groove” mode of the neuropeptide relaxin-3 (H3)-RXFP3 receptor underlies a series of intracellular signalling events and provides a blueprint for molecular mimicry that can drive drug discovery. Investigating a series of stapling approaches and combining with intranasal delivery, we have demonstrated the potential of this system in eating and CNS disorders. A complete perspective from in-silico design to brain uptake capacities using novel multi-specific therapeutic modalities will be presented. This may be the first preclinical demonstration of a macrocyclic or hydrocarbon constrained peptide across the blood-brain barrier.


5:50 Close of Conference

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