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 (20 C/D Foyer) 

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

32 A/B

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

Yudin_AAndrei 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

Lokey_SScott 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 Exploring Conformational Space of Macrocycles: From the Solid State to Solution

Hawkins_PaulPaul Hawkins, Head, Scientific Solutions, OpenEye Scientific

Tools for conformational sampling of macrocycles are validated against conformations from the solid state. This approach, while straightforward, provides no performance data for the solution state, where most pharmaceutically-relevant data is obtained. Here we describe our approach to macrocycle conformation sampling, and compare it to other methods on conformations from the solid state. We show how this approach can incorporate structural data from solution and be used to solve NMR structures of macrocycles in solution.

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

  • 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

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: Modelling or empirical property-based selection?
  • What is missing? What technologies could rapidly enhance macrocycle discovery and development? Better modelling, more efficient synthesis, more diverse hits...?

6:15 Close of Day

6:30 Dinner Short Courses*

*Premium or separate registration required.

Thursday, April 11

8:00 am Morning Coffee

8:45 Plenary Session Welcome Remarks from Event Director

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

8:50 Plenary Keynote Introduction

Timothy Craig, PhD, HarkerBio

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

Jansa_PPetr 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.

Fidelta 11:45 FideltaMacro™: Macrolide Inspired Macrocycles as Promising Templates for Unmet Medical Needs

Tanja Poljak, PhD, Group Leader, Medicinal Chemistry, Fidelta Ltd.

This talk will present recent results on our macrolide inspired macrocyclic library prepared using FideltaMacroTM technology including in vitro screening, pharmacokinetic data as well as in vivo proof of concept data. Inhibition of IL17A/IL17R interaction will be presented as a case study of targeting protein-protein interactions. Other major achievements such as a novel macrocyclic compound that showed efficacy in the mouse bleomycin model and additional novel oral antibacterials with in vivo demonstrated Gram-negative activity data will be discussed.

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

Johnson_TTed. 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.

12:30 Enjoy Lunch on Your Own

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

Poster Awards Sponsored by Domainex


2:15 Chairperson’s Remarks

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

2:20 Macrocyclic Inhibitors of Pim1/2 Kinase

Liping H. Pettus, PhD, Principal Scientist, Chemistry Research & Discovery, Amgen

Pim-1/2 kinases have been pursued as therapeutic targets for the treatment of hematologic malignancies. Starting from a non-selective HTS hit, we developed a series of 13-membered macrocycles. Systemic exploration of the macrocyclic linker led to the identification of AM-0944 as a selective inhibitor of Pim-1/2 kinases that was potent in vitro (pBAD IC50 25 nM) and efficacious in KMS-12-BM mouse xenograft model (100% TGI at 100 mg/kg daily PO dose).

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

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

Neurotensin mediates opioid-independent analgesia via the NTS1 and NTS2 receptors. Careful exploration of optimal sites of cyclization on Neurotensin 8-13 led to two distinct series of macrocyclic pharmacological probes. Series 1 possesses low nM potency for both NTS1 and NTS2, while series 2 is associated with low nM potency for NTS2 and >1,000-fold selectivity vs NTS1. In vivo, these series allowed separation of the desired analgesia from the undesired hypotension and hypothermia.

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

Spellmeyer_DDavid 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

Ahmed_AAdel 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

Felden_BBrice 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

Marwari_SSubhi 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