Constrained Peptides and Macrocyclics

This meeting covers the progress and challenges of accessing new chemical space – the middle space – to find molecules with drug potential that are bigger than small molecules but smaller than biologics. The hope is that these middle-sized molecules are big enough for more specific interactions with protein-protein interaction surfaces but small enough to penetrate the cell, reach intracellular drug targets and be orally bioavailable. However, theory is still meeting practice. Researchers continue to refine the ’rules’ and properties for the best design of this class of molecules which mainly consist of constrained peptides and synthetic macrocyclics.

Final Agenda

Choose 2 Short Courses
or 1 Symposium and 2 Conferences/Training Seminars

Wednesday, September 26

7:00 am Registration Open and Morning Coffee (Foyer)

Inhibiting Intracellular Protein-Protein Interactions
Fairfax B

8:00 Welcome Remarks

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

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

8:10 KEYNOTE PRESENTATION: Peptide Drug Hunter: An Extraordinary Trek into Intracellular Target Space

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

Macrocyclic peptides can modulate intracellular protein-protein interaction target space; however, achieving cell permeability is challenging and is hindering their therapeutic potential. Accordingly, we have focused a multidisciplinary effort on macrocyclic peptides to understand their structure-cell permeability relationships. As a benchmark and model system, we have studied a series of analogs of ATSP-7041, a stapled peptide dual antagonist of MDM2 and MDMX, to evaluate and correlate their biological, biophysical, permeability and metabolic stability properties.

8:40 Modulation of Intracellular Protein-Protein Interactions with Bicyclic Peptides

Pei_DehuaDehua Pei, PhD, Professor of Chemistry and Biochemistry, The Ohio State University

We are developing bicyclic peptides as a novel class of inhibitors against intracellular protein-protein interactions (PPIs), which are challenging targets for conventional drug modalities. These bicycles feature highly active cell-penetrating peptides (CPPs) in one ring for cellular entry and specific target-binding sequences in the second ring. Potent, selective, proteolytically stable, and cell-permeable bicyclic peptidyl inhibitors have been generated against a variety of intracellular proteins including protein tyrosine phosphatases, peptidyl-prolyl isomerase, K-Ras, and NFkB essential modulator.

9:10 Targeting a Metabolic Vulnerability in Parasitic Nematodes with Nucleic Acid-Encoded Peptide Libraries

Inglese_JamesJames Inglese, PhD, Director, Assay Development and Screening Technologies, National Center for Advancing Translational Sciences (NCATS), NIH

iPGM is the nematode isozyme of the human glycolytic enzyme, phosphoglycerate mutase, and represents a potential drug target for tropical diseases. Small molecule high throughput screening efforts by others have failed to identify inhibitors. We used mRNA-display affinity selection to identify isozyme-selective phosphoglycerate mutase ligands, termed Ipglycermides that potently inhibit the catalytic activity of all nematode iPGM orthologs tested to date. Progress in the pharmacological evaluation of ipglycermide analogs aimed at developing a therapeutics agent will be discussed.

9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

10:25 Stapled Peptides Targeting MCL-1 and BFL-1 to Reactivate Apoptosis in Cancer

Loren D. Walensky, MD, PhD, Professor, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, Harvard Medical School

The “helix-in-groove” mode of protein-protein interaction underlies a series of oncogenic signaling events that drive human cancer. Indeed, a nearly universal mechanism of apoptotic suppression in cancer is governed by the entrapment of pro-death helices by the surface grooves of anti-apoptotic BCL-2 family proteins. Here, we developed both non-covalent and covalent stapled peptide inhibitors to dissect and target the apoptotic blockades imposed by MCL-1 and BFL-1, yielding new drug prototypes for cancer therapy.

10:55 Discovery of ALRN-6924, a first-in-class MDMX and MDM2 Dual Inhibitor Stapled Peptide in Clinical Trials

Vincent Guerlavais, PhD, Director, Medicinal Chemistry, Aileron Therapeutics

The challenge of designing potent macrocyclic peptides able to efficiently modulate intracellular protein-protein interactions is well documented. A technology platform named stapled peptide has recently emerged that can address and solve inherent limitations of peptides particularly their poor cell permeability. To illustrate this, the unique drug-like properties of ALRN-6924, a cell-penetrating alpha-helical stapled peptide that equipotently disrupts the interaction between the p53 tumor suppressor protein and its endogenous inhibitors MDMX and MDM2, will be presented.

11:25 Late Breaking Presentation

11:55 Enjoy Lunch on Your Own

1:15 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

Non-Peptidic Synthetic Macrocyclics
Fairfax B

1:50 Chairperson’s Remarks

Alec Flyer, PhD, Investigator III, Global Discovery Chemistry, Novartis Institutes BioMedical Research

1:55 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.

2:25 Structure-Based Design of Small-Molecule Macrocycles

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

Despite having diverse chemical structures, macrocycles are often considered as a single chemotype. A recent survey covering macrocyclic drugs and clinical candidates captures their diversity in both chemical structure and discovery provenance. We are interested in the structure-based design of purely synthetic small-molecule macrocycles, an area of drug discovery that has not been heavily explored. We present simple metrics that facilitate the detection and prioritization of bound ligands that may be particularly suited to macrocyclization. Representative examples of such macrocyclic-like compounds will be presented for discussion.

2:55 Selected Poster Presentation: Selenoethers as Surrogates of Disulfide and Thioether Bonds: Applications in Cyclic Peptides

Aline Dantas de Araujo, PhD, Senior Postdoctoral Fellow, David Fairlie Group, Institute for Molecular Bioscience, University of Queensland, Australia

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced (Grand Ballroom)

4:05 Discovery of Potent and Orally Bioavailable Macrocyclic Peptide-Peptoid Hybrid CXCR7 Modulators

Boehm_MMarkus 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.

4:35 Lessons for the Design of Synthetic Macrocycles from Machine Learning

Whitty_AAdrian Whitty, PhD, Professor, Biochemistry, Boston University

We identified several novel macrocycle-specific molecular descriptors based on structural or physicochemical features, for assessing macrocyclic chemotype diversity and predicting the key ADME property of membrane permeability. These descriptors should help inform the design of pharmaceutically useful macrocycles or macrocycle libraries, which because they contain non-traditional drug chemotypes, need rules beyond those considered in traditional assessments of drug likeness. I also describe various machine learning techniques we used for evaluating the utility of the descriptors we identified.

5:05 Interactive Breakout Discussion Groups - View Details

Room: Constitution B

Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic.

Table 10: Conformational Searching and Macrocycles

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

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

Table 11: 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
  • Applications of machine learning

Table 12: Drug Development Challenges of Stapled Peptides and Synthetic Macrocyclics

Moderator: Vincent Guerlavais, PhD, Director, Medicinal Chemistry, Aileron Therapeutics



  • Lead op challenges unique to stapled peptides or macrocyclics
  • Planning ahead: making it easier for formulation/scale-up
  • Converting a drug candidate into a macrocyclic 

6:05 Welcome Reception in the Exhibit Hall with Poster Viewing (Grand Ballroom)

7:10 Close of Day

Thursday, September 27

7:30 am Registration Open and Morning Coffee (Foyer)

Cyclic Peptide Design Challenges
Fairfax B

8:00 Chairperson’s Remarks

Susanne Saalau, PhD, Senior Director, Biochemistry and Screening, FOG Pharma

8:05 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.

8:35 Measuring Cytosolic Penetration Using the Chloroalkane Penetration Assay

Kritzer_J_MCYJoshua A. Kritzer, PhD, Associate Professor, Department of Chemistry, Tufts University

Cell penetration is a major obstacle for developing peptide, protein and nucleic acid therapeutics. Most commonly used techniques for measuring cell penetration are qualitative, and most cannot distinguish cytosolic material from material trapped at the cell surface or in endosomes. We have devised a new technique, the chloroalkane penetration assay (CAPA), that measures penetration to the cytosol in a high-throughput, quantitative manner. Here, we describe the advantages and disadvantages of CAPA and demonstrate some of its applications.

9:05 Breakout Discussions Report-Back

9:35 Coffee Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

10:20 Identification of Novel Constrained Peptides and Scaffolds against Cap-Dependent Translation

Christopher J. Brown, PhD, Research Scientist, p53lab, A*STAR

The eIF4F complex is frequently dysregulated in human cancers leading to an increase in cap-dependent translation, which causes the upregulation of key oncogenic related proteins. Rational stapled peptide design and constrained peptide phage display have identified new modalities that inhibit eIF4F activity. These activi-ties have enabled an alternative interaction motif against the eIF4E:4G interface critical for eIF4F assembly to be discovered, enabling the exploration of new chemical space.

10:50 Artificial Intelligence Designed TLR4 Peptide Activators

Lerner_ImmanuelImmanuel Lerner, PhD, CEO, Pepticom

The use of artificial intelligence (AI) for the target based discovery of novel peptides. Relevant results and background regarding discovery projects will be presented with emphasis on the discovery and validation of TLR4 agonist cyclic peptides (composed of D,L and non natural amino acids).

11:20 Enjoy Lunch on Your Own

11:50 Conference Registration Open (Foyer)

12:20 pm Plenary Keynote Program (Constitution Ballroom)

2:00 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

2:45 Close of Conference