Cambridge Healthtech Institute’s 6th Annual

Macrocyclics & Constrained Peptides

Cell-Penetrating ‘Bigger’ Molecules

April 4-5, 2018 | Hilton Bayfront | San Diego, California


Many biopharmaceutical researchers are now turning to new chemical space – the middle space – to find molecules with drug potential. Compounds in this space are bigger than small molecules, enabling more specific interactions with PPI surfaces. But they are smaller than biologics, enabling cell-penetration, oral availability and the ability to reach intracellular targets. Making these medium-sized compounds cyclic enhances their solubility and gives rise to the class of compounds now commonly referred to as synthetic macrocyclics and constrained peptides. However, theory is still meeting practice. Researchers continue to refine the ‘rules’ and properties for the best design of this class of molecules. This meeting covers the progress and challenges in the field.

Final Agenda

Wednesday, April 4

12:30 pm Registration

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


1:30 Welcome Remarks

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

1:35 Chairperson’s Opening Remarks

Hiroaki Suga, PhD, Professor, Department of Chemistry, School of Science, The University of Tokyo

1:40 Lessons for the Design of Synthetic Macrocycles from Machine Learning

Adrian_WhittyAdrian Whitty, PhD, Professor, Biochemistry, Boston University

We are exploring whether there are structural or physicochemical features specific to macrocycles, beyond those properties considered in traditional assessments of druglikeness, that influence the ADME properties of these non-traditional drug chemotypes, and thus can help inform the design of pharmaceutically useful macrocycles or macrocycle libraries. I will describe several novel macrocycle-specific molecular descriptors that we have developed, and our use of various Machine Learning techniques to evaluate the utility of these descriptors for assessing macrocycle chemotype diversity, and for predicting the key ADME property of membrane permeability.


2:10 Physical Chemical Properties for Drug Design in Beyond Rule of Five Chemical Space

Marina_ShalaevaMarina Shalaeva, PhD, Principal Scientist, Medicinal Design, Pfizer

New concepts and methods are being developed for evaluation and modulation of properties of Bro5 compounds to achieve acceptable PK/PD in drug candidate. In particular, the PLRP-S method for estimating lipophilicity and ionization in nonpolar membrane-like environment is described. A fast chromatographic assay is used to asses lipophilicity-ionization patterns of lipophilic, low solubility Bro5 compounds in combination with pKa by MCE, while EPSA and ElogD are used to drive passive permeability and drug efficiency (lipE).

2:40 Lipophilic Permeability Efficiency (LPE) Enables the Identification and Quantification of Structural Effects on Macrocycle Permeability

Matthew_NaylorMatthew R. Naylor, PhD, LIFA Postdoctoral Fellow, Eli Lilly & Co.

Macrocycle scaffold structure determines the balance between lipophilicity and aqueous solubility in the pursuit of bRo5 therapeutics capable of passive cell permeability. Current techniques to identify such structure are time-intensive (NMR analysis) or challenging on large peptides (in silico prediction). Combining a simple hydrocarbon lipophilicity measurement with a predictor of aqueous solubility, Lipophilic Permeability Efficiency (LPE) quantifies the intrinsic ability of diverse bRo5 scaffolds to hide backbone or sidechain polarity for cell permeability.

3:10 Conformational Sampling of Macrocycles in Solution

Paul HawkinsPaul Hawkins, PhD, Head, Scientific Solutions, OpenEye Scientific Software

Some types of macrocyclic molecules have been shown to be orally bioavailable ligands for targets such as GPCRs and protein-protein interfaces, which requires then to be able to permeate cell membranes effectively. The means by which high molecular weight macrocycles are able to be membrane permeable has been the subject of some recent study, but no clear conclusions have yet been reached. In this presentation we discuss how to model effectively the conformational properties of macrocycles in different environments and how experimental data gathered in solution, particularly from NMR, can be used to improve that sampling.

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

4:30 Property-Based Drug Design beyond Ro5 - Lessons Learned from AbbVie’s Drugs and Compound Collection

Phil_CoxPhil Cox, PhD, Senior Principal Scientist, Chemistry Group Leader, Discovery Chemistry and Technology, AbbVie, Inc.

This presentation will focus on the lessons learned from an initiative to analyze AbbVie’s internal database of compounds beyond Ro5 (including macrocycles).

5:00 Rationalizing the Passive Membrane Permeability of Cyclic Peptides

Sereina_RinikerSereina Riniker, PhD, Assistant Professor, Laboratory of Physical Chemistry, ETH Zürich

The hypothesis for the passive membrane permeability of cyclic peptides involves the interconversion between "open" conformations and "closed" conformations prior to the entering of the membrane. Using kinetic models based on molecular dynamics (MD) simulations in polar and apolar environments, a rationale for the “permeability cliff” presented by the natural product cyclosporine A and its synthetic derivative cyclosporine E as well as for a recently published series of cyclic decapeptides is provided.

5:30 Breakout Discussions

In this session, 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: Conformational Searching and Macrocycles

Maxwell D. Cummings, PhD, Senior Principal Scientist, Computational Chemistry, Discovery Sciences, Janssen R&D
Paul Hawkins, PhD, Head, Scientific Solutions, OpenEye Scientific Software

  • Is the binding mode known, suspected or unknown?
  • Selection of conformers and conformer sets: energy, RMSD, properties…
  • Aspects of computational search methods relevant to macrocycles

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's represents good potency, and does this depend on library chemistry?
  • Specialized/biased versus general purpose libraries

Topic: The Future Role of Macrocycles in Drug Discovery

Moderator: Mark Parisi, Executive Director, ASINEX

The interest in macrocycles has grown greatly over the past few years: the number of macrocyclic platform companies has grown from 2 to 20+, interest from academia to pharma has increased significantly, computational chemistry has contributed by creating and refining “new rules,” etc. Can we project where we are headed given the current situation? Join this table to discuss:

  • Macrocycles: the past, present, and future
  • Incorporating macrocyclic chemistry into screening strategy
  • Applying filters: Ro5, bRo5, or no Ro5 (among other filters….)?

6:15 End of Day

6:30 Dinner Short Courses*

*Separate registration required

Thursday, April 5

8:00 am Breakfast Presentation: Improvements in NMR Approaches to Fragment Based Screening

Donna BaldisseriDonna Baldisseri, Senior Applications Scientist, Bruker BioSpin

FBDD is a powerful search engine for identification of fragments that bind to disease relevant target proteins ultimately leading to drug candidates. NMR-based FBDD screening requires compound library validation, preparation of hundreds of samples per campaign, automated acquisition, processing of thousands of spectra, and their analysis for binding assessment. Here is described the streamlined solutions offered by Bruker, automating this pipeline to improve the speed and productiveness of FBDD screening for the pharmaceutical industry.

8:45 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

8:50 Plenary Keynote Introduction

Chris PetersenChris Petersen, CTO,

8:55 PLENARY KEYNOTE: Targeting Ras and MYC for the Treatment of Cancer

Stephen Fesik
Stephen Fesik, PhD, Professor of Biochemistry, Pharmacology, and Chemistry, Orrin H. Ingram II Chair in Cancer Research, Vanderbilt University School of Medicine
Two of the most important targets in cancer are Ras and MYC. However, both of these highly validated cancer targets are thought to be undruggable. In this presentation, I will discuss our approaches for targeting both of these proteins directly and indirectly using fragment-based methods and structure-based design.

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


10:40 Chairperson’s Remarks

Maxwell D. Cummings, PhD, Senior Principal Scientist, Computational Chemistry, Discovery Sciences, Janssen R&D

10:45 FEATURED PRESENTATION: The RaPID Discovery of Bioactive Pseudo-Natural Peptides

Hiroaki Suga
Hiroaki Suga, PhD, Professor, Department of Chemistry, School of Science, The University of Tokyo
This lecture will describe the most recent development in the genetic code reprogramming technology that enables us to express pseudo-natural peptides. The technology involves (1) efficient macrocyclization of peptides, (2) incorporation of non-standard amino acids, such as N-methyl amino acids, (3) reliable synthesis of libraries with the complexity of more than a trillion members, (4) rapid discovery of potent bioactive pseudo-natural peptides by the RaPID system (or PDPS).

11:15 Lead Optimization of Natural-Product Derived NaV1.7 Inhibitory Disulfide-Rich Peptides

Kaustav_BiswasKaustav Biswas, PhD, Principal Scientist, Hybrid Modality Engineering, Amgen, Inc.

My talk details Amgen’s program directed at inhibition of the voltage-gated sodium channel NaV1.7 for pain and itch using hits from a venom screen. We identified novel toxin peptides from tarantula venom which have disulfide-rich folded motifs. Using a combination of positional scanning and peptide-ion channel molecular docking studies, we will discuss the discovery of synthetic analogues with activity in ex vivo and in vivo behavioral NaV1.7-dependent models.

11:45 Selected Poster Presentation: The Evolution of Apratoxins: Total Synthesis of Natural Products and Analogues with Improved Anticancer Activity

Qi-Yin Chen, University of Florida


12:00 pm Discovery of Potent and Orally Bioavailable Macrocyclic Peptide-Peptoid Hybrid CXCR7 Modulators

Markus Boehm, PhD, Associate Research Fellow, Medicinal Chemistry, Pfizer

While several small molecules have been identified that modulate the activity of CXCR7, an attractive drug target for a variety of disease indications, peptidic macrocycles may provide additional advantages in terms of potency, selectivity, and reduced off-target activity. We report on a series of peptidic macrocycles that bind to CXCR7 and also incorporate an N-linked peptoid functionality in order to overcome the poor permeability associated with peptides. The peptoid group also enabled us to explore side chain diversity well beyond that of natural amino acids.

Schrodinger 12:30 Luncheon Presentation: Evaluation of Free Energy Calculations for the Prioritization of Macrocyclic Cyclophilin Inhibitors

Janet PaulsenJanet Paulsen, PhD, Senior Scientist, Applications Science, Schrödinger

Macrocycles are often used to drug difficult targets, such as PPIs or balance desirable drug properties. Synthesis of these molecules can require significant effort with no guarantee that the molecule will have improved properties or meet project goals. Here, I will present a blinded retrospective investigation, performed in collaboration with Gilead, targeting cyclophilin for Hepatitis C. FEP+ successfully predicted relative binding free energies, rank-ordered compounds and explained non-intuitive SAR for a class of mini-sanglifehrins.

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


2:15 Chairperson’s Remarks

Adrian Whitty, PhD, Professor, Biochemistry, Boston University

2:20 Cell Penetration Profiling for Biotherapeutics

Joshua_KritzerJoshua Kritzer, PhD, Associate Professor, Chemistry, Tufts University

Several classes of biomolecules have emerged as exciting potential therapies, but their development has been impeded by imprecise measurements of intracellular delivery. The Kritzer lab has devised a new method for quantitating cell penetration, the ChloroAlkane Penetration Assay (CAPA). CAPA is inexpensive and high-throughput, and it can quantitate penetration to individual cellular compartments. We are using CAPA to comprehensively profile cell penetration for diverse biomolecules and drug delivery systems.

2:50 Catching Cyclic Peptides in Action at the Ribosome

Jordan Carelli, PhD, formerly Graduate Student, Jack Taunton Lab, UCSF; currently Senior Scientist, Oncology RU, Pfizer
Ternatin-4 and didemnin B are unrelated cyclic peptides that kill cancer cells by binding the eukaryotic elongation factor 1A (eEF1A)•aa-tRNA•GTP ternary complex. I will present our efforts in the Taunton lab to elucidate the molecular mechanisms by which ternatin-4 and didemnin B inhibit protein translation. Despite sharing an allosteric binding site on eEF1A, ternatin-4 and didemnin B differentially impact eEF1A conformational dynamics in vitro, and have distinct effects on cancer-derived and non-malignant cells.

3:20 Polar Hinges as Functionalized Conformational Constraints in (Bi)Cyclic Peptides

Alex_HooseAlex Hoose, PhD, Post-doctoral Research Associate, Liskamp Group, School of Chemistry, University of Glasgow

We wish to devise (cyclic) peptides and peptidomimetics as protein-protein interactions (PPI) inhibitors. Polar hinges have been developed for cyclization of peptides leading to bicyclic peptides and cyclized peptides with improved solubility and biological activity. Increasingly, we note that a good aqueous solubility of peptides is an absolute prerequisite not only to be able to handle and purify our target peptides but it is also crucial for biological activity characterization.

3:50 Refreshment Break

4:20 Cyclotide Antagonists of the HDM2-HDMX RING-Mediated E3 Ligase

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

The cyclotide scaffold has a tremendous potential for the development of therapeutic leads based on their extraordinary stability and potential for grafting applications. We will show an example, where a large cyclotide-based genetically encoded library was used to screen for low nanomolar antagonists for the Hdm2-HdmX RING-mediated E3 ligase activity. We will also present different strategies to improve the cellular uptake and pharmacokinetic profiles of bioactive cyclotides.

4:50 Constrained Oligomers Targeting the Ubiquitin-Proteasome Pathway

Thomas_KodadekThomas Kodadek, PhD, Professor of Chemistry; Associate Dean of Graduate and Post-Doctoral Studies, The Scripps Research Institute

5:20 Chemo-enzymatic Synthesis of Highly Constrained Multicyclic Peptides

Marcel_SchmidtMarcel Schmidt, Industrial PhD Candidate, Van't Hoff Institute of Molecular Sciences, University of Amsterdam

The increasing number of macrocyclic peptides currently being investigated as prospective therapeutics requires efficient, cost-effective routes for their synthesis. We have developed a flexible and broadly applicable chemo-enzymatic strategy that enables the efficient, scalable assembly of (multi)cyclic peptide macrocycles. We successfully employed omniligase-1-catalyzed peptide backbone cyclization for the synthesis of a plethora of peptides, ranging from naturally occurring multicyclic peptides (e.g. cyclotide MCoTI-II) to multicyclic peptides containing non-natural scaffolds with bifunctional biological activity (e.g. tri- and tetracycles).

5:50 End of Conference

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