The relatively new class of drug-like compounds – synthetic macrocyclics and constrained peptide therapeutics -- are garnering great interest in the drug development industry because of their theoretical mix of favorable properties. Their middle size (.5 -2 kilodaltons) makes it more likely that they can cross the cell membrane and reach intracellular targets. Yet these molecules have the safety/tolerability advantage of biologics because they are bigger than typical 'small molecule' drug agents and therefore capable of more specific interactions with their targets. And unlike small molecules, they have more potential surfaces with which to disrupt PPI targets. The cyclic nature of macrocyclics and constrained peptides affords stability and the potential to be developed into oral-based medicines. A few oral-based macrocyclic or constrained peptide compounds are in clinical trials against intracellular targets, but none have yet reached the market. This meeting covers the technological advances that are enabling these compounds to progress and addresses the challenges that still remain.

Final Agenda

Tuesday, April 25

12:30 pm Registration

DESIGNING FOR CELL-PERMEABILITY AND OTHER Ro5 FEATURES

1:30 Chairperson’s Remarks

Jan Kihlberg, Ph.D., Professor, Organic Chemistry, Uppsala University

1:40 FEATURED PRESENTATION: Macrocyclic Secondary Structure: Permeability and Chemical Biology

Spiros Liras, Ph.D., Vice President, Head, Cardiovascular Metabolism, RDRU and Discovery Network, Pfizer, Inc.

Emerging themes regarding permeability of macrocycles displayed in defined secondary structures will be discussed, specifically for alpha helices. In addition, the impact of macrocycles secondary structure on pharmacology in the context of the GLP-1 receptor will be discussed.

2:10 Decoding Rules of Passive Membrane Permeability in Cyclic Peptides: Lessons from Natural Products and Beyond

Scott Lokey, Ph.D., Professor, Chemistry and Biochemistry, University of California, Santa Cruz

The best known cyclic peptide with drug-like membrane permeability is cyclosporine A, but a survey of natural products suggests that there may be many others. These compounds offer a treasure trove of structural motifs that can be mimicked in non-natural cyclic peptides to bias them toward passive membrane permeability. I will present our efforts to capitalize on our understanding of the factors that govern passive permeability in cyclic peptides inspired by natural products.

2:40 Permeability of Semi-Peptidic Macrocycles

Eric Marsault, Ph.D., Professor, Medicinal Chemistry and Pharmacology, University of Sherbrooke

Macrocycles have recently attracted a high level of interest for their unique potential ability to combine large surface areas and suitable druglike properties. While macrocyclic peptides have been thoroughly analyzed to define permeability rules, there is no systematic study on semi-peptidic macrocycles, which constitute a rapidly increasing subclass among clinical candidates. We will discuss recent data on the structure-permeability relationship of macrocycles composed of a tripeptide tethered with a nonpeptidic linker.

 

3:10 Conformational Sampling of Macrocycles: Recent Progress

Paul Hawkins, Ph.D., Head, Scientific Solutions, OpenEye Scientific Software

Macrocyclic molecules have been shown to be orally bioavailable ligands for targets such as GPCRs and protein-protein interfaces. Greater exploitation of macrocycles in drug discovery has been stymied by a lack of computational methods to investigate their properties, including their conformational space. Here we present some recent work on conformational sampling of macrocycles that attempts to balance sampling near conformations likely to be relevant to biological activity with the time required for the calculation.

 

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

4:30 Late-Breaking Presentation: Role of Conformational Flexibility for Cell Permeability Beyond the Rule of 5

Jan Kihlberg, Ph.D., Professor, Organic Chemistry, Uppsala University

Analysis of approved drugs indicates that dynamic intramolecular shielding of polar surface area (PSA) is important for cell permeability at MW >700 Da. Moreover, an excellent correlation was found between the minimum solvent accessible 3D PSA and permeability for a set of drugs with MW 700-1000 Da. Inspection of their crystal structures suggested that flexibly linked aromatic side chains are particularly useful in design of drugs that adapt their PSA to the environment.

 

4:45 PANEL DISCUSSION: Reaching Consensus on New Chemical Rules for Macrocycles

Moderator: Mark Parisi, MS, Executive Director, Chemistry, Asinex

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

Robert Foglesong, Ph.D., Director, Business Development, Selcia, Ltd

Jan Kihlberg, Ph.D., Professor, Organic Chemistry, Uppsala University

Contest Winner - this could be YOU!

There has been much discussion, speculation, and general commentary on New Rules for Macrocycles and an academic-industrial group (Asinex-Boston University-Pharma) has come together to explicitly address this topic. This panel will gather input from the macrocyclic community with the goal of arriving at a definitive new set of rules for macrocycles submitted for publication for the benefit of researchers in the Macrocyclic Drug Discovery community. Given the focus on group involvement, we (Asinex) are inviting all members of the Macrocyclic research community to submit their ideas as we will choose one applicant to be on the panel; please access information on how to enter the panelist competition via the following link : DrugDiscoveryChemistry.com/Asinex-Panel

5:30 Breakout Discussions

6:15 Close of Day

6:30 Dinner Short Courses*

*Separate registration required

Wednesday, April 26

7:45Plenary Breakfast Presentation: NMR in Fragment-Based Lead Discovery (FBLD)

Stefan Jehle, Ph.D., Product Manager, Bruker BioSpin

NMR is ideally suited for detecting low affinity fragments in solution for FBLD and allows quality control of the screening library on the fly. The large dynamic range with respect to the MW of the target and binding affinities enables its application to a broad range of targets. During this presentation, we will show straight forward NMR methods in FBLD for non-experts, basic principles, data acquisition, data analysis, automation options, software solutions and assay development.

8:30 PLENARY KEYNOTE PRESENTATION

Drug Discovery and Pan-Assay Interference Compounds (PAINS)

Jonathan B. Baell, Ph.D., Professor, Medicinal Chemistry, Monash University

I will discuss issues around the PAINS filter that we published in 2010 and since then has generated much discussion in the industry. The PAINS filter helped explain the difficulties with certain compounds that many hit-to-lead medicinal chemists around the world, principally in academia and small biotechs but to some extent in big pharma also, were encountering. However, because some known drugs contain PAINS, there is the fear that such filters may be too stringent.

9:30 Coffee Break in the Exhibit Hall with Poster Viewing

STRATEGIES FOR CONSTRAINING PEPTIDES

10:40 Chairperson’s Remarks

Scott Lokey, Ph.D., Professor, Chemistry and Biochemistry, University of California, Santa Cruz

10:45 Cyclic Peptides as Specific Immunomodulators

Dehua Pei, Ph.D., Professor, Department of Chemistry and Biochemistry, The Ohio State University

I will present our work on developing cyclic peptide inhibitors against the interactions between calcineurin-NFAT, NEMO-IKK, and/or TNFa-TNFR.

11:15 Tether-Functionalized Stapled Peptides for the Estrogen Receptor/Coactivator Interaction

Terry Moore, Ph.D., Assistant Professor, Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago

Stapled peptides are often designed so that the staple replaces two non-interacting residues, although there are now several examples where the staple can replace interacting, hydrophobic residues. We have developed novel stapling amino acids that can mimic hydrophobic amino acids, and we have incorporated these into sequences derived from steroid receptor coactivator. These peptides inhibit the interaction of coactivator with both wild-type and recently described somatic mutant estrogen receptors.

11:45Selected Poster Presentations

12:00 pm Development of Drug-Like Cotransins: Structure-Activity and Structure-Pharmacokinetic Studies of Cyclic Depsipeptide Modulators of Sec61

Phillip Patrick Sharp, Ph.D., Postdoctoral Scholar, Laboratory of Jack Taunton, Cellular and Molecular Pharmacology, University of California, San Francisco

Cotransins, cyclic heptadepsipeptide allosteric modulators of Sec61, are potentially powerful compounds for targeting canonically ‘undruggable’ therapeutic targets. However, developing cotransins that have high substrate selectivity and good pharmacokinetic profiles is challenging. This presentation will disclose novel synthetic modifications of cotransin structure that augment both their substrate selectivity and pharmacokinetics.

 

12:30 Luncheon Presentation: Computationally-Driven Structure-Based Drug Design

Victoria Feher, Ph.D., Global Head, Application Science and Modeling Services, Schrödinger

Water plays a key role in the binding of small molecules to proteins; therefore, it is critical to have a clear understanding of active site water networks in drug design. We will present examples, both retrospective and prospective, of the successful use of accurate binding site water energetics, through FEP analyses, to evaluate druggability, identify ‘hot spots,’ assess opportunities for bridging water interactions, and facilitate the design of compounds with improved potency and selectivity.

 

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

COMPOUNDS WITH THERAPEUTIC PROMISE

2:15 Chairperson’s Remarks

Ashok Bhandari, Ph.D., Vice President, Chemistry, Protagonist Therapeutics

2:20 Discovery & Development of PTG-100, an Oral Peptide Antagonist of α4β7 Integrin, for the Treatment of Inflammatory Bowel Disease

Ashok Bhandari, Ph.D., Vice President, Chemistry, Protagonist Therapeutics

We discuss the discovery of PTG-100, a potential first-in-class oral peptide antagonist of α4β7 integrin in clinical trials for the treatment of patients with ulcerative colitis and Crohn’s disease. PTG-100 alters trafficking of gut homing T cells in animal models of colitis and was discovered by our oral peptide technology platform. Target engagement was assessed in the peripheral blood of colitis and healthy mice, and translated to the demonstration of pharmacodynamic proof-of-concept in a Phase I trial with normal healthy volunteers.

2:50 Discovery of Potent Cyclophilin Inhibitors Based on Structural Simplification of Sanglifehrin A

Vicky Steadman, Ph.D., Director of Drug Discovery, 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.

3:20 Novel Cyclic Antibiotic Drug Leads Inferred from a Bacterial Toxin

Brice Felden, Ph.D., Research Head, Rennes University, Inserm

Staphylococcus aureus is a commensal bacterium and pathogen that causes community-acquired, healthcare-related, and nosocomial infections in humans. We previously discovered a linear peptide toxin that induces deaths to competing bacteria (both Gram-positive and negative), but also to host human cells. We present our work around synthesizing a series of 20 compounds; our most promising derivatives are small cyclic pseudopeptides with inconsequential toxicity to human cells and mice, enhanced stability in human sera, and sharp antibacterial activity on infected mice.

3:50 Refreshment Break

4:20 Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Opioid Peptide and Peptidomimetic Design

Steven Ballet, Ph.D., Associate Professor, Departments of Chemistry and Bio-Engineering Sciences, Vrije Universiteit Brussel

Constraining the conformation of flexible peptides is a proven strategy to increase potency, selectivity, and metabolic stability. In this presentation, we focus on cyclic aromatic amino acids in which the side chain is connected to the peptide backbone to provide control of χ1- and χ2-space (as opposed to the usual focus of constraining the backbone dihedral angles). The manifold applications for cyclized analogues of the aromatic amino acids within peptide medicinal chemistry are showcased with examples of enzyme inhibitors and ligands for G protein-coupled receptors.

4:50 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.

5:20CANCELLED:Novel Routes for the Synthesis of Medium and Large Fused Ring Systems as Chemical Navigators for Phenotypic Screening

Taleb Al Tel, Ph.D., Director, Sharjah Institute for Medical Research, University of Sharjah, UAE

I will be describing our efforts directed towards designing unprecedented and diverse macrocyclic compounds collections (medium and large sized ring systems) possessing privileged architectures that represent the basic core of many biologically significant compounds. Furthermore, anticancer and antimalarial activities of these compounds will also be presented.

5:50 Close of Conference

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