3rd Annual

Macrocyclics and Constrained Peptides

Bigger, Better, But hopefully still Oral, Small Molecules

April 22-23, 2015 


Recent advances combining biological and chemical approaches to create libraries of small, synthetic macrocyclic molecules have created a new class of therapeutically promising compounds that exhibit desireable ‘middle ground’ characteristics – small enough to pass through the cell membrane and reach intracellular targets, with the potential to be delivered orally; but large enough to have better specificity for disrupting protein-protein interactions. This conference explores this emerging class of molecules and discusses the challenges they face as drug candidates. Join fellow drug discovery scientists for this day-and-a-half meeting that is in the second half of our larger Drug Discovery Chemistry event. 


This meeting was an eye-opener for me to see how collectively drug delivery scientists can work
with medicinal chemists to bring new pharmaceutical products more effectively to the market.

Hayat O., Professor, University of Illinois at Chicago

Day 1 | Day 2 | Download Brochure | Speaker Biographies | Register 

Wednesday, April 22

12:30 pm Registration


1:30 Chairperson’s Remarks

Nicholas Terrett, Ph.D., CSO, Ensemble

1:40 FEATURED SPEAKER: Understanding Permeability of Peptide and Peptidomimetic Macrocycles

Spiros LirasSpiros Liras, Ph.D., Vice President, Worldwide Medicinal Chemistry, CVMED, Pfizer

Peptidic macrocycles represent a potential lead option for difficult drug targets including protein-protein interaction inhibitors and class B GPCRs. As part of a network with leading researchers in academia we set out to develop principles for the rational design of permeable and orally bioavailable macrocycles. We have developed strategies for the generation of orally bioavailable peptidic macrocycles which include N-methylation, hydrophobic shielding of polar functionality, hydrogen bond donor management with intramolecular hydrogen bond networks and incorporation of peptidomimetic fragments. Application of these design strategies in case studies, identification of key limitations and future opportunities for this modality will be discussed in this presentation.

2:10 Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates

Jan KihlbergJan Kihlberg, Ph.D., Professor, Department of Chemistry, BMC, Uppsala University, Sweden

Analysis of a comprehensive set of drugs and clinical candidates having MW >500 Da demonstrate significant opportunities for discovery of cell permeable and orally bioavailable drugs in physicochemical space far beyond the rule of 5 (bRo5). As compared to Ro5 compliant drugs, those bRo5 may modulate different kinds of targets, in particular ones having flat and groove shaped binding sites. Interestingly, macrocycles appear to have features that provide special opportunities in bRo5 drug space.

2:40 Towards Design Rules for Macrocycles

Adrian Whitty, Ph.D., Department of Chemistry, Biomolecular Engineering Research Center, Boston University

The potential utility of synthetic macrocycles as drugs, particularly against challenging targets such as protein-protein interactions, has been widely discussed. We have analyzed the binding modes of a representative set of macrocycle-protein complexes. The results allow us to propose specific guidelines for the design of synthetic macrocycles libraries possessing structural and physicochemical features likely to favor strong binding to protein targets and also good bioavailability.

3:10 Approaching Macrocyclic Chemical Space through Non-Conventional Routes

ScottBreiningScott Breining, Ph.D., Senior Medicinal Chemist, Medicinal Chemistry, Asinex Corporation

At Asinex, over a 5 year period of macrocyclic synthetic development, we have learned many lessons, developed new approaches, and also created a platform that uses macrocycles as the core element in the design of novel peptidomimetic molecules. These structures have the correct geometry and substitution characteristics to align the requisite functional groups in three dimensions and are thus able to disrupt key elements of the PPI interface. This talk will focus on how this strategy addresses an unmet need in drug discovery. We will also touch on lessons learned in our history of macrocyclic development.

3:40 Celebratory 10th Annual Refreshment Break in the Exhibit Hall with Poster Viewing

4:20 Constrained Cyclic Peptides: Conformation vs. Bioavailability

David P. FairlieDavid P. Fairlie, Ph.D., Professor and Head, Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland

We live in a new age of injectable peptide drugs. Exponential growth in protein/peptide therapeutics will continue due to the increasing need to target larger, shallower, interacting protein surfaces. To achieve potency and high selectivity, larger molecules with additional chemical foliage are required. Cyclic peptides provide opportunities to increase molecular size and interactions, while constraining ligands into pre-organized protein-binding conformations. What limits the conversion of cyclic peptides into potent, selective and orally bioavailable drugs?

4:50 Structural Basis of Macrocycle-Enzyme Interaction

Markus Seeliger, Ph.D., Assistant Professor, Pharmacological Sciences, Stony Brook University

We have determined the co-crystal structures of unusually specific macrocyclic inhibitors of protein kinases and proteases. These macrocycles were derived from a DNA-templated library of macrocycles. Currently, there are few synthetic macrocycles in clinical use. In fact, there is only a small number of protein co-crystal structures with macrocyclic compounds. Our recently published co-crystal structures of Src and IDE in complex with macrocyclic inhibitors gives new insights into the way these compounds achieve specificity.

5:20 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: Designing Drug-like Compounds Beyond Rule of 5

Moderator: Jan Kihlberg, Ph.D., Professor, Department of Chemistry, BMC, Uppsala University, Sweden

  • What are the key properties compounds should have?
  • How can computational chemistry contribute?
  • What are the biggest hurdles?

Topic: Cyclic Peptides for PPI Targets

Moderator: Nir Qvit, Ph.D., Postdoctoral Fellow, Chemical and Systems Biology, Stanford University

  • Cyclization methods
  • Peptide modification strategies
  • Different PPI targets
  • Therapeutic challenges

Topic: How Macrocyclics Interact with Proteins

Moderator: Adrian Whitty, Ph.D., Department of Chemistry, Biomolecular Engineering Research Center, Boston University

  • Towards design rules for macrocycles
  • Identification of protein targets for macrocycle drugs
  • Examples in the literature/development

6:20 Close of Day

6:30 Dinner Short Courses*

*Separate registration required; please see 'Short Courses' page for details 

Day 1 | Day 2 | Download Brochure | Speaker Biographies | Register 

Thursday, April 23

8:00 am Morning Coffee


Fragment-Based Drug Discovery: A Fifteen Year (Re-)Evolution

Harren JhotiHarren Jhoti, Ph.D., President & CEO, Astex Pharmaceuticals

Fragment-based discovery has now been successfully established as an alternative approach to HTS and has produced multiple drug candidates that are in clinical trials. Some of the appealing features of the approach include the ability to efficiently sample chemical space and to produce drug candidates that have superior physicochemical properties. In this talk I will provide a perspective on how Fragment-Based drug discovery evolved over the last 15 years and challenged conventional thinking in Drug Discovery.

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


10:10 Chairperson’s Remarks

John A. McCauley, Ph.D., Director, Medicinal Chemistry, Merck & Co., Inc.

10:15 Exploring Macrocycles for Protein-Protein Interaction Targets: the Discovery of Novel Bifunctional XIAP Antagonists

Nicholas TerrettNicholas Terrett, Ph.D., CSO, Ensemble

Macrocycles are found widely in nature and several are marketed as drugs with good pharmaceutical properties. This talk will describe how Ensemble can rapidly generate millions of synthetic macrocycles using DNA-programmed chemistry, and how they are efficiently screened against protein-protein interaction targets to identify hit compounds and SAR. The novel approach will be illustrated with successful examples of lead discovery programs, including the discovery of novel dimeric macrocyclic XIAP antagonists.

10:45 A Novel Cyclic Peptide Drp1 Inhibitor Diminishes Aberrant Mitochondrial Fission

Nir QvitNir Qvit, Ph.D., Postdoctoral Fellow, Chemical and Systems Biology, Stanford University

I will address several key issues regarding constrained peptides, such as, cyclization, peptidomimetic and peptide modification. Excessive mitochondrial fission is associated with the pathology of a number of neurodegenerative diseases. Therefore, inhibitors of aberrant mitochondrial fission could provide important research tools in addition to potential leads for drug development. Using a rational approach, we designed a novel and selective cyclic peptide inhibitor of excessive mitochondrial fission. This novel cyclic peptide inhibits Drp1 enzyme activity and blocks Drp1/Fis1 interaction in vitro and in cultured neurons. I will present some unpublished data from our lab to support my conclusions.

OpenEye_Vertical11:15 Conformational Sampling of Macrocycles at Speed: An Unmet Need

Paul Hawkins, Ph.D., Applications Science Group Leader, OpenEye Scientific Software

This presentation will focus on relevant conformational sampling of macrocycles at high speed. In our solution we combine an unbiased sampling method with efficient global optimization to sample thoroughly the relevant conformational space of macrocycles on a time scale of minutes rather than hours. 

11:30 Late Breaking Presentation

12:00 pm Macrocycle Conformational Analysis, A Tool For Rational Macrocycle Design

DanSindhikaraDan Sindhikara, Senior Scientist, Structure-based ADME/Macrocycles, Schrödinger

We present an approach for efficient and accurate exploration of the conformational space of both peptidic and non-peptidic macrocycles. A comprehensive understanding of the conformational properties of a given macrocyclic ligand allows for the accurate prediction of membrane permeability and bioavailability. It also opens the door for rational macrocycle design in terms of both cyclization strategies as well as rigidification of existing macrocycles to further enhance their binding potency. We present our current progress towards these goals in terms of algorithm performance, development of analysis techniques, and synthesis with complementary tools. 

12:30 Walk and Talk Luncheon in the Exhibit Hall with Poster Viewing (last chance for viewing) and Poster Awards


1:40 Chairperson’s Remarks

Eric Marsault, Ph.D., Professor, Pharmacology, University of Sherbrooke

1:45 p53/HDM2 Case Study: Macrocyclic Organo-Peptide Hybrids as Molecular Scaffolds for Targeting PPIs

Rudi FasanRudi Fasan, Ph.D., Associate Professor, Department of Chemistry, University of Rochester

This talk will present novel methodologies developed in our group for constructing macrocycles with a hybrid peptidic/non-peptidic backbone through the embedding of non-proteogenic, synthetic elements into genetically encoded peptidic frameworks. In recent studies, we established that these macrocyclic scaffolds can readily accommodate a-helical protein binding motifs. A case study will be discussed in which this strategy was applied to obtain macrocyclic inhibitors of the p53:HDM2 interaction that display dual specificity against the HDMX homolog as well as favorable proteolytic stability and cell penetration properties.

2:15 A Macrocyclic Peptide Inhibitor of Complement C5 as an Alternative to Monoclonal Antibody Therapy

Douglas A. Treco, Ph.D., President and CEO, Ra Pharmaceuticals, Inc. 

2:45 Refreshment Break


3:00 Nanocyclix Approach towards Unexplored Kinases: Identification of RIP2 and SIK2 Inhibitors for Application in Auto-Immune and CNS Disorders

Jan HoflackJan Hoflack, Ph.D., CSO, Oncodesign Biotechnology

Oncodesign’s chemical biology approach using its macrocyclic chemistry platform has allowed the identification of potent and selective inhibitors for RIP2 and SIK2 kinases. The molecules have been used as chemical probes to validate the potential of these novel targets. Data will be presented that demonstrate the potential role of RIP2 as a target of interest in auto-immune diseases and for SIK2 in neuroprotection/ageing. The discovery and optimization of the inhibitors will be presented.

3:30 PF-06463922, a Novel Small Molecule Inhibitor of ALK/ROS1 with Preclinical Brain Availability and Broad Spectrum Potency against ALK-Resistant Mutations

Ted W. JohnsonTed W. Johnson, Ph.D., Research Fellow, Medicinal Chemistry, Pfizer Oncology

PF-06463922, a novel macrocyclic inhibitor of ALK/ROS1, demonstrated low nanomolar inhibitory activity against a panel of ALK kinase domain mutants representing all of the patient crizotinib resistant mutations reported to date. Successful optimization of molecular weight and lipophilic efficiency leveraging structure-based drug design techniques led to ligands with overlapping broad spectrum potency, low transporter efflux, and brain penetration. PF-06463922 is currently in Phase 1/2 clinical trials.

4:00 Discovery of SB1578 - A JAK2 Small Molecule Macrocycle for Autoimmune Diseases

Anthony D. WilliamAnthony D. William, Ph.D., Senior Scientist, The Agency for Science, Technology and Research (A*STAR)-ICES

SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also demonstrates potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. Herein the design and optimization of the macrocyclic Jak2/Flt3 inhibitor will be discussed including the biochemical and cellular activities of SB1578 that translate into its high efficacy in rodent models of arthritis.

4:30 Close of Conference 

Day 1 | Day 2 | Download Brochure | Speaker Biographies | Register