4th Annual

Macrocyclics and Constrained Peptides

Bigger, Better, But hopefully still Oral, Small Molecules

April 20-21, 2016

Macrocyclics and Constrained Peptides icon

The newer, synthetic macrocyclic and constrained peptide compounds (ranging in size from .5 -2 kilodaltons) offer the promise of being the ‘ideal’ class of compounds for new drug entities. Their cyclical shape enables solubility and stability affording them the possibility to be developed into oral medications and most are small enough to cross the cell membrane to reach intracellular targets, where many of the causes and solutions to diseases reside. And because of macrocyclics’ slightly larger size than typical small molecules, they offer more specificity and have greater chances of disrupting protein-protein interactions. However, theory has yet to be fully realized. Solubility and cell permeability issues are still being addressed. This meeting will focus on the remaining challenges, cover the new targets being addressed with macrocyclics and provide updates on a few early examples of compounds advancing in drug development.

Final Agenda

Wednesday, April 20

12:30 pm Registration


1:30 Chairperson’s Remarks

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

1:40 FEATURED PRESENTATION: How to Design Non-Peptidic Cell Permeable Macrocycles

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

Macrocycles provide unique opportunities to modulate difficult targets like protein-protein-interactions. Analysis of macrocyclic drugs and clinical candidates and experimental profiling of >200 de novo-designed macrocycles revealed how functional groups and substituents, stereochemistry and dynamic, intramolecular interactions in the 3D conformations are linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modelling and conformational analysis now provides a rational approach to design of cell-permeable, non-peptidic macrocycles with potential for oral administration.

2:10 Passive Membrane Permeability in Cyclic Peptides: New Rules for a New Chemical Space

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

The prospect that macrocyclic peptides that lie well outside the Rule of 5 can have drug-like, passive cell permeability has stimulated much effort toward understanding the physical basis for the behavior of such outliers. I will discuss our latest results from a series of systematic studies using a variety of synthetic, biophysical, and analytical tools, designed to probe the specific structural and physicochemical constraints that govern ADME behavior in macrocycles in the MW~1000 range.

2:40 Computational and Physical Properties of Orally Bioavailable Cyclic Peptides

Alan_MathiowetzAlan M. Mathiowetz, Ph.D., Director, Pfizer Worldwide Medicinal Chemistry – Cardiovascular and Metabolic Diseases

An increasing number of orally bioavailable cyclic peptides have been discovered in recent years, providing us with an opportunity to identify the design principles for achieving improved permeability in this traditionally challenging physical property space. A variety of computational parameters and measured physical properties will be discussed, describing their relationship to permeability and other ADME properties – both across a broad dataset of compounds and for specific published orally bioavailable peptides.

Schrodinger3:10 Technologies Enabling Macrocycle Design

Dan Sindhikara, Ph.D., Senior Scientist, Schrödinger

Macrocycles can offer attractive properties such as defiance of Ro5 guidelines while posing new challenges due to their unique topology. Combining state-of-the-art modelling software with bleeding-edge macrocycle-specific technology, we are paving the way to rational macrocycle design. Our tools focus on our new high-speed, accurate macrocycle sampling algorithm able to rigorously sample macrocycles within seconds to minutes. Leveraging the macrocycle sampling protocol, we can now quickly do physics-based passive-permeability predictions, docking, and binding free energy calculations. Further we are developing technology to quickly generate virtual macrocycle libraries for screening containing millions of compounds or more.

Aptuit3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Computer-Aided Macrocycle Design

Matthew_JacobsonMatthew Jacobson, Ph.D., Professor, Pharmaceutical Chemistry, University of California, San Francisco

I will discuss the central challenge in computational modeling of macrocycles—predicting the three-dimensional structure of the backbone—with applications to permeability prediction; structure-based or ligand-based design; and the creation of virtual libraries. Examples will include cyclic peptides, polyketides, and other classes of natural product and synthetic macrocycles.

5:00 From Haystack to Needle: Using Encoded Libraries at GSK

Christopher_PhelpsChristopher Phelps, Ph.D., Manager, Drug Design & Selection Boston, RD Platform Technology & Science, GSK

In 2005 scientists at Praecis Pharmaceuticals first realized the power of DNA encoded libraries with successful selections of triazine scaffolds against p38 kinase. A year later, the same team screened four targets from GSK, and the outcome of that collaboration was the acquisition of Praecis and the first integration of encoded library technology (ELT) into the hit ID engine of a major pharmaceutical company. This presentation will review some milestones of that journey and the technical advances in library chemistry, selection methods, and informatics that were enabled within GSK.

5:30 Breakout Discussions

In this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers. Check our website in February to see the full listing of breakout topics and moderators.

Topic: Targeting PPIs with Macrocyclics

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

  • Membrane permeability/oral bioavailability
  • Medchem approaches to macrocycle optimization
  • Plasma half-life
  • Large-scale production

Topic: Macrocyclic Library Challenges

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

  • Pros and Cons of different large library types: DNA-encoded (chemical), RNA-display (ribosomal), split-pool OBOC methods (and associated encoding strategies)
  • Enriching for membrane-permeable molecules in macrocyclic libraries: how to maximize diversity within a desirable property space?
  • Approaches to the parallel synthesis of discrete macrocycles: automation platforms for synthesis and purification and their rate-limiting steps

Topic: The Extra Challenge of Lead Optimization with Macrocycles

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

  • Is traditional med chem-based optimization with macrocyclic analogues feasible?
  • Can molecules be “compartmentalized” for optimization purposes?
  • Are pre-made macrocycle libraries better?

6:15 Close of Day

6:30 Dinner Short Courses*

*Separate registration required.

Thursday, April 21

Hitgen7:45 am Breakfast Presentation: DNA Encoded Libraries and the Economics of Early Stage Drug Discovery: Managing the Economics of Serendipity

Barry_MorganBarry A. Morgan, Ph.D., Visiting Professor, Institute for Molecular Medicine, University of Texas Health Sciences

A review of FDA approved drugs, and the increased cost of drug discovery over the past few decades highlights the unsustainability of the current model for bringing new medicines to clinical practice. We will review the factors involved in this analysis, and present a case for DNA encoded library technology bringing disruptive change to early stage drug discovery.

8:00 Morning Coffee


Cell-Penetrating Miniproteins

Gregory VerdineGregory L. Verdine, Ph.D., Professor, Departments of Stem Cell and Regenerative Biology, Chemistry and Chemical Biology, and Molecular and Cellular Biology, Harvard University

It has been estimated that as few as 10-15% of all potential targets are targetable in vivo by either biological or small molecules. To address this deficiency, we and FOG Pharmaceuticals are developing cell-penetrating mini-proteins, molecules that combine the ability of proteins to target large flat surfaces, with the ability of small molecules to penetrate cells. Progress on the development of cell-penetrating mini-proteins will be reviewed in this talk.

Advanced Cellular Dynamics9:30 Coffee Break in the Exhibit Hall with Poster Viewing



10:10 Chairperson’s Remarks

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

10:15 Synthesis and Screening of Vast Libraries of DNA-Encoded Macrocycles

Thomas_KodadekThomas Kodadek, Ph.D., Professor, Chemistry and Cancer Biology, The Scripps Research Institute, Scripps Florida

Macrocycles that mimic some of the favorable properties of natural products are of great interest as chemical probes and drug leads. As a potentially rich source of such compounds, we have created vast DNA-encoded combinatorial libraries of structurally complex macrocycles displayed on 10 µm beads. These libraries can be screened by incubation with fluorescently labeled target proteins and unlabeled competitor proteins and hits can be isolated using a flow cytometer. This system constitutes a powerful tool for the discovery of bioactive macrocycles as well as a method for assessing the relative merits of macrocycles and linear molecules as protein ligands.

10:45 Step-Wise Selection of Peptide Binders Using High-Density Peptide Arrays

Jighar_PatelJigar Patel, Ph.D., Director, Technology Innovation, Roche NimbleGen Inc.

We will describe a step-wise selection method using L and D amino acids synthesized on High Density Peptide arrays using Streptavidin as a case example. We have identified various binding peptides, and have determined their co-crystal structures. All studied peptides were found to bind to the same biotin-binding pocket of streptavidin and pre-incubation of streptavidin with biotin completely abolishes any of the peptide binding. Discovery of multiple peptides in both linear and cyclic forms with different sequences bound to the biotin site suggests that these peptides can demonstrate a significant plasticity in creating specific contacts with the same target.

11:15 Moving Macrocyclic Research Forward: New Rules and Drug Discovery Application

Roman Kombarov, Ph.D., Head, Business Development, ASINEX Corporation

Over the past 6 years, we have synthesized over 30,000 macrocyclic compounds and optimized synthetic techniques with special focus on reaction types used for scaffold synthesis. This talk will relate lessons learned and stress two main directions in our macrocyclic research: the first is to refine a set of rules for cellular permeability and the second involves drug discovery application of macrocyclic chemistry with a special focus on the areas of oncology and anti-bacterial research.

11:45 Joining Chemistry and Biology to Make Macrocycles

James_NaismithJames H. Naismith, Ph.D., Professor, Chemical Biology, St. Andrews University

I will report our progress on combining enzymes, some of which have re-engineered, from the patellamide and patellamide-like pathways with organic chemical synthesis. Our objective is access novel peptide/non-peptide hybrid macrocyclic compounds that would otherwise be very challenging to make. These compounds are being designed as novel inhibitor starting points as they can encode particular epitopes in a conformationally tuneable scaffold. I will also report work on combining solid phase synthesis with the enzymes.

OpenEye NEW12:15 pm 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.

12:45 Luncheon Presentation (Opportunity Available)

1:30 Ice Cream Refreshment Break in the Exhibit Hallwith Poster Awards


2:15 Chairperson’s Remarks

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

2:20 Lorlatinib (PF-06463922), a Macrocyclic ALK/ROS1 Inhibitor for the Treatment of Resistance Mutations and Brain Metastasis

Ted W. Johnson, Ph.D., Senior Principal Scientist, Oncology Chemistry, Pfizer San Diego

PF-06463922, a novel macrocyclic inhibitor of ALK/ROS1 currently in Phase I/II clinical trials, demonstrated low nanomolar inhibitory activity against a panel of ALK kinase domain mutations with overlapping CNS activity to treat brain metastasis. Structure-based drug design, CNS drug design and efficacy data will be presented.

2:50 Cyclohexylgriselimycin: A Synthetic and New Anti-Tuberculosis Drug Candidate

Evelyn_FontaineEvelyne Fontaine, Ph.D., Laboratory Head, Infectious Diseases, Medicinal Chemistry, Sanofi

We present a case study in peptide chemistry: from a poorly drug-like parent compound, the natural cyclodepsipeptide Griselimycin discovered 50 years ago, we’ll report how we solved the metabolic lability, improved the oral PK and balanced the antibacterial potency with lipophylicity and solubility. Total synthesis including SPPS and macrocyclisation was used to prepare more than 230 cyclodepsipeptides, and also 200G of cyclohexylgriselimycin. NMR 3D structure of Cyclohexylgriselimycin, RX-structure in complex with DnaN and MOA elucidation will be presented.

3:20 Refreshment Break

3:40 Macrocycle Design for PD1-PD1L and p53-MDM2

Alexander Dömling, Ph.D., Professor, Drug Design, University of Groningen

Protein protein interactions are a key target area for macrocycles due to their often difficult druggability by classical approaches such as small molecules. MDM2-p53 for examples comprise a well-structured interface with 700A2 buried interface while PD1-PD1L is very flat and featureless comprising 2000A2 buried interface. Here we report the design and synthesis of PD1-PD1L and p53-MDM2 directed macrocycles including their protein complexes. PD1-PD1L is a game changing target in immuno-oncology.

4:10 Orally Stable GI restricted Peptides for InflammatoryBowel Diseases

Greg Bourne, Ph.D., Senior Research Fellow, Chemistry, Protagonist Therapeutics

Inflammatory bowel disease (IBD) offers clinically validated targets for gut restricted drug development. Protagonist has applied its technology platform and expertise in peptide and medicinal chemistry to develop novel, potent, target specific and orally stable gut restricted peptides for α4β7 integrin and IL23-receptor. These peptides have minimal /no systemic exposure, yet are active in preclinical IBD models. We will discuss strategies in developing these orally stable peptide antagonists for GI restricted diseases.

4:40 Macrocyclic Drug Candidates for Lung Diseases andNovel Antibiotics

Daniel_ObrechtDaniel Obrecht, Ph.D., CSO, Pharmaceutical Research, Polyphor Ltd.

We have established two complementary, fully proprietary macrocycle technologies that yield synthetically accessible compounds that are amenable to a rapid and efficient optimization process, and have a proven potential to provide innovative drug candidates for complex target classes. I present two case studies: POL6014 in Phase I development for cystic fibrosis and other rare lung diseases, is a highly potent and selective macrocyclic inhibitor of human neutrophil elastase (HNE) and POL7080, a novel breakthrough antibiotic against Gram-negative bacteria.

5:10 Close of Conference