2017 Archived Content
Constrained peptides and macrocyclics represent a relatively new class of drug compounds that are smaller than biologics or protein therapeutics but bigger than the ‘small molecule’ class of traditional drugs. Their ‘middle size’ and the synthetic or natural constraints that give them a ring structure is supposed to make them the Goldilocks or ‘just right’ set of new therapeutic modalities because they should be small enough to cross the cell membrane, unlike biologics, and therefore not be limited to only acting on cell-surface targets and they have the potential to be developed into oral therapeutics. At the same time these molecules are large enough to have the safety/tolerability advantage of biologics and the ability to better disrupt protein-protein interactions and therefore are more useful for targeting the ‘undruggable’ protein complexes that much of new drug discovery is taking aim at. Join us at Cambridge Healthtech Institute’s Inaugural Constrained Peptides and Macrocyclics symposium to witness how this class is living up to its promise and discuss the challenges that lie ahead.
Final Agenda
Monday, September 25
7:00 am Registration Open and Morning Coffee
7:55 Welcome Remarks
Anjani Shah, Ph.D., Conference Director, Cambridge Healthtech Institute
8:00 Chairperson’s Opening Remarks
Lauren Monovich, Ph.D., Senior Investigator, Global Discovery Chemistry, Novartis
8:10 Properties of Peptidic Macrocycles Beyond the Rule-of-5
Alan M. Mathiowetz, Ph.D., Director, Pfizer Worldwide Medicinal Chemistry – Cardiovascular and Metabolic Diseases
Peptidic macrocycles with properties beyond the Rule-of-5 (BRo5) have the potential to be effective modulators of difficult targets. Oral delivery of such molecules is challenging, however, and requires a balance of competing properties such as permeability, clearance, and potency. This talk provides an overview of structure/property trends we have found spanning multiple series of BRo5 macrocycles and highlights both promising and challenging areas.
8:40 ADME Considerations for Non-peptidic Macrocycles
Adrian Whitty, Ph.D., Professor, Biochemistry, Boston University
The last several years have seen a significant upsurge of interest in the use of synthetic macrocycles in drug discovery, and particularly in their potential as inhibitors of difficult targets such as protein-protein interactions. I will discuss progress towards understanding what structural and physicochemical properties of synthetic non-peptidic macrocycles confer good pharmaceutical properties, and particularly good aqueous solubility coupled with passive membrane permeability.
9:10 Peptidic and Non-Peptidic Macrocycles for Challenging Targets in Drug Discovery
Steffen Weinbrenner, Ph.D., Head Drug Discovery, Drug Discovery, Polyphor Ltd
The talk will give insight into how macrocycles as new therapeutic modalities are complementing the chemical space and help to identify chemical matter for difficult targets and target classes. A particular focus will be given how macrocycles offer chemical matter beyond the rule of 5, still being cell penetrating and orally bioavailable. A case study on macrocycle MedChem optimization will be presented.
9:40 Networking Coffee Break with Poster Viewing
10:10 Facile Peptide Cyclization and Bicyclization via Iminoboronate Chemistry
Jianmin Gao, Ph.D., Associate Professor, Chemistry, Boston College
We recently reported a powerful strategy for peptide cyclization which takes advantage of formation and reduction of iminoboronates (J. Am. Chem. Soc., 2016, 138, 2098). Assisted by the boronic acid substituent, intramolecular iminoboronate formation readily proceeds under physiological conditions to allow for spontaneous peptide cyclization and bicyclization. While formation of iminoboronate is reversible, peptide (bi) cyclization can be made permanent via mild reduction. The resulting (bi)cyclic peptides display novel amino-boronate motifs that can promote structural rigidification and facilitate target recognition. Importantly, this iminoboronate-based cyclization allows for facile generation of libraries of peptide macrocycles, which can be applied to ligand discovery for a variety of targets.
10:40 Design of Technology-Compatible Cyclic Peptide Scaffolds with Oral Bioavailability
Lauren Monovich, Ph.D., Senior Investigator, Global Discovery Chemistry, Novartis
Traditionally, permeable macrocyclic peptides have been identified by discrete synthesis and careful side chain variation of privileged, natural product scaffolds. More recently, the basic principles governing passive permeability were applied to the prospective design of macrocyclic peptide scaffolds with oral bioavailability. However, there remains the broad challenge of chemical diversity sufficient to enable regular identification of novel protein ligands. Herein, we present macrocyclic peptide scaffolds with ribosomal library-compatible amino acids and experimentally validated oral bioavailability.
11:10 Sponsored Presentation (Opportunity Available)
11:40 Enjoy Lunch on Your Own
1:10 pm Chairperson’s Remarks
Maxwell D. Cummings, Ph.D., Senior Principal Scientist, Computational Chemistry, Discovery Sciences, Janssen R&D
1:20 FEATURED PRESENTATION: Macrocyclized Extended Peptides for Tankyrase Inhibition
Heike Laman, Ph.D., Associate Professor, Department of Pathology, Cambridge University
1:50 Discovery of Potent Cyclophilin Inhibitors Based on Structural Simplification of Sanglifehrin A
Vicky Steadman, Ph.D., Director of Drug Discovery, Cypralis
Sanglifehrin, a complex macrocyclic natural product (MW>1000, 17 chiral centers), is a potent inhibitor of cyclophilins, a target for HCV. Through a structure-guided medicinal chemistry approach, potent, simplified and drug like macrocyclic inhibitors of cyclophilin were identified (MW~500 and 4 chiral centers). The design, synthesis and biological activity of these partially peptidic macrocycles will be discussed.
2:20 Ipglycermides: Novel Macrocyclic Peptide Inhibitors of Microorganism Phosphoglycerate Mutase
James Inglese, Ph.D., Director, Assay Development and Screening Technologies, National Center for Advancing Translational Sciences (NCATS), NIH
This presentation will describe the discovery and mechanism of action of the first inhibitor class for an essential glycolytic enzyme, co-factor independent phosphoglycerate mutase (iPGM), an important target in several infectious organisms, including parasitic nematodes, trypanosomes and the gram positive bacteria Staphylococcus aureus. The enzyme has been considered “undruggable” due to unsuccessful attempts to identify inhibitors from small molecule high throughput screening (HTS). As an alternative approach to HTS we sought to explore the exceedingly vast chemical space available from nucleic acid-encoded cyclic peptide libraries.
2:50 Networking Refreshment Break with Poster Viewing
3:30 Targeting Intracellular Protein-Protein Interactions with Structure-Based Designed Macrocyclic Peptides
David J. Earp, J.D., Ph.D., President and CEO, 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.
4:00 A Macrocyclic Peptide for Complement-Mediated Diseases
Doug Treco, Ph.D., Director, President, CEO and Co-Founder, RA Pharma
Inappropriate activation of complement C5 leads to RBC destruction in the rare, acquired disease paroxysmal nocturnal hemoglobinuria (PNH), and has been implicated in other serious indications. RA101495 is a potent, synthetic, macrocyclic peptide that binds C5 and inhibits its activation through a novel mechanism. A Phase I study in healthy volunteers has been completed, supporting the advancement of this product into Phase II studies in patients with PNH and other indications.
4:30 Design and Application of a DNA-Encoded Macrocyclic Peptide Library
Zhengrong Zhu, Ph.D., Scientific Leader, PTS-DDS-NCE, GlaxoSmithKline
A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.5×1012 members composed of 4-20 natural and unnatural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. Based on selection data some peptides were selected for resynthesis without DNA tag and their activity was confirmed.
5:00 Close of Symposium
5:00 Pre-Conference Dinner Short Course Registration
Click here for details on short courses offered.