Constrained Peptides and Macrocyclics

Cambridge Healthtech Institute 第1回

第15回Discovery on Targetの一翼を担うイベント


Final Agenda


· September 25 Symposium: Constrained Peptides and Macrocyclics

· September 25 Short Course: Enabling Macrocyclic Compounds for Drug Discovery: Opportunities, Challenges and Strategies

· September 26-27 Conference: Lead Generation Strategies

· September 27-28 Conference: Autoimmune and Inflammation Drug Targets

· September 27 Short Course: Introduction to Targeted Covalent Inhibitors

· September 28-29 Symposium: Tackling Rare Diseases

Monday, September 25

7:00 am Registration Open and Morning Coffee

Making Macrocyclics Peptide-Like

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 Addressing the Solubility Challenge of Macrocyclic Drug Candidates

Adrian Whitty, Ph.D., Professor, Biochemistry, Boston University

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

Making Peptides Cyclic

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

Case Studies of Macrocyclic Peptides for Specific Targets

1:10 pm Chairperson's Remarks

Alan M. Mathiowetz, Ph.D., Director, Pfizer Worldwide Medicinal Chemistry - Cardiovascular and Metabolic Diseases

1:20 FEATURED PRESENTATION: Macrocyclized Expended Peptides for Tankyrase Inhibition

Laura Itzhaki, Ph.D., Professor, Department of Pharmacology, 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

Case Studies of Macrocyclic Peptides for Specific Targets (Cont.)

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.

* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。

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