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
Wednesday, September 26
7:00 am Registration Open and Morning Coffee (Foyer)
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
Dehua 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
James 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)
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
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.
2:25 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
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.
4:35 Lessons for the Design of Synthetic Macrocycles from Machine Learning
Adrian 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
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)
8:00 Chairperson’s Remarks
Susanne Saalau, PhD, Senior Director, Biochemistry and Screening, FOG Pharma
8:05 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.
8:35 Measuring Cytosolic Penetration Using the Chloroalkane Penetration Assay
Joshua 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
Immanuel 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