2014 Archived Content

2nd Annual

Macrocyclics and Constrained Peptides Drug Discovery

Novel Peptide Therapeutics

April 24-25, 2014 


The main excitement over the newer synthetic/non-naturally occurring smaller macrocyclic molecules as drug candidates is their middle ground promise. Like traditional ‘small molecules,’ macrocyclic peptides can be delivered orally and pass through the cell membrane to reach intracellular targets. Yet they have some of the advantages of bigger molecules like biologics such as the ability to better disrupt protein-protein interactions while still allowing for high potency and specificity. Cambridge Healthtech Institute’s second annual Macrocyclics and Constrained Peptides Drug Discovery meeting will explore this emerging class of molecules (as well as constrained peptides that can be considered a subset of macrocyclic peptides) and the types of cellular targets they are being developed against. Case studies of macrocyclic compounds that originated from different types of libraries will also be presented with a focus on the types of chemical optimizations needed to progress from hits to lead candidates.

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

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Thursday, April 24 - Day 1



12:30 pm Registration


Properties of a ‘Good’ Macrocyclic 

1:30 Chairperson’s Opening Remarks

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


» 1:40 Featured Presentation: Unexpected Structure-Permeability Relationships in Cyclic Peptides Inspired by Natural Products: Charting Islands of Bioavailability Beyond the Rule of 5s

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

Many cyclic peptide natural products share a common chemical feature, backbone N-methylation, which serves to enhance lipophilicity and proteolytic stability, although the impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated in detail. I will present our latest research on the use of NMR and computational methods to examine the interplay between structure and conformation to determine membrane permeability in natural product-inspired cyclic peptides.

2:10 Building a Natural Product-Inspired Macrocyclic Toolbox to Hunt for Modulators of
Protein-Protein Interactions

Prabhat AryaPrabhat Arya, Ph.D., Professor, Chemistry and Chemical Biology, DRILS University of Hyderabad, India

A case study of a novel macrocyclic molecule that prevents mitochondrial damage in beta cells through a gain/correction of function will highlight our approach of targeting PPIs with natural product-inspired small molecules that are 3D in shape with 2-4 stereogenic centres and acceptable pharma complexity. The more traditional flat, aromatic chemical toolbox, while fine for accessing the deep and well-defined pockets of traditional enzyme targets, is proving inadequate for signaling pathway-based targets, such as protein-protein or protein-DNA/RNA- interactions.


2:40 Design and Synthesis of Macrocyclic Tera-Peptide Mimetics for PPI and Antibacterial Applications

Genis_DmitryDmitry Genis, Ph.D., CEO, ASINEX

Compounds with mid- and large-sized rings have long been considered by medicinal chemists as a discrete class of molecules, not only due to their interesting physico-chemical and biological properties, but also due to the challenge of their synthesis. In this talk, we present the design of novel medchem-like macrocyclic scaffolds based on non-conventional macrocyclization chemistries and the use of pre-designed macrocycles for lead generation with special emphasis on protein-protein interaction targets and antibacterial research.

3:10 Macrocycles in Small Molecule Drug Discovery

Max CummingsMax Cummings, Ph.D., Principal Scientist, Discovery Sciences, Janssen

Macrocycles are receiving increased attention in small molecule drug discovery. Macrocyclization allows for larger small molecules that may not meet standard calculated property criteria, and macrocycles are frequently invoked as a magic bullet for the vast frontier of protein-protein interactions. A discussion around the topic of macrocycles in small-molecule drug discovery will be presented, with the HCV compounds Simeprevir and TMC647055 as examples to frame the more general discussion.

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

4:20 Macrocyclic Analogues of G Protein-Coupled Receptor, Apelin, for Biased Signaling 

EricMarsaultEric Marsault, Ph.D., Professor, Pharmacology, University of SherbrookeEric Marsault, Ph.D., Professor, Pharmacology, University of Sherbrooke


4:50 Exploiting  3D Peptide Mimetics for Drug Discovery

Wim Meutermans, Ph.D.,  Vice President of Discovery, Alchemia Ltd.

Pyranose is a versatile 3-dimensional scaffold with high stereogenic and sp3 content. Though not a macrocycle, the pyranose scaffold is ideally suited to position substituents in a great variety of 3D arrangements in space, similar to macrocycles or cyclic peptides. The resulting molecules are similar in size, rigidity, and 3D complexity, accessing new drug-like space. Alchemia has screened its array of 15,000 such diversely-shaped compounds against a broad range of internal targets and in a multi-target partnership with AstraZeneca. The presentation will include in vitro and in vivo efficacy case studies. 


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.

Topic 1: The Extra Challenge of Lead Optimization with Macrocycles

Moderator: Max Cummings, Ph.D., Principal Scientist, Discovery Sciences, Janssen

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

Topic 2: Macrocyclic Library Challenges

Adrian Culf, Ph.D., Research Scientist, Medicinal Chemistry, Atlantic Cancer Research Institute
Peter Timmerman, Ph.D., CSO, Pepscan Therapeutics

• Biological v.chemical v. combo libraries
• Pros and cons of various shapes of macrocyclics
• Partnering for libraries v. in-house development

Topic 3: Targeting PPIs with Macrocyclics

Moderator: Prabhat Arya, Ph.D., Professor, Chemistry and Chemical Biology, DRILS University of Hyderabad, India

• Intracellular/solubility challenges
• Importance of 3D

6:20 Close of Day

6:30 Dinner Short Courses*

Friday, April 25 - Day 2


7:30 am Morning Coffee


Targeting Membrane Proteins with Macrocyclics 

8:00 Chairperson’s Remarks

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

8:05 Synthetic Macrocyclic, Protease-Resistant Peptides that Mimic Endocrine Hormones and Bind Receptors

Danielle GuarracinoDanielle Guarracino, Ph.D., Assistant Professor, Chemistry, The College of New Jersey

A deficiency of cyclic peptide hormone vasopressin poses the continuous threat of dehydration and loss of electrolyte balance in a rare form of diabetes. In contrast, overactive cyclic peptide hormone oxytocin, similar in structure, has been linked to prostate enlargement, autism, and anxiety disorders. We developed macrocyclic compounds that structurally mimic these hormones, with changes intended to promote stability and potency. Each mimicking compound had moderate abilities to compete with immobilized vasopressin for binding its G-protein coupled receptor (GPCR).

8:35 Structures of P-Glycoprotein in Complex with Cyclopeptide Inhibitors and Stimulators Reveal Flexible Binding Sites and Conformations

Qinghai ZhangQinghai Zhang, Ph.D., Associate Professor, Integral Structural and Computational Biology, The Scripps Research Institute

P-glycoprotein is a primary ATP-binding cassette (ABC) transporter causing multidrug resistance in many cancer cells. We describe the design, library synthesis and screening of conformationally constrained cyclopeptides, from which we characterized potent inhibitors and transporters for P-glycoprotein. Several new crystal structures revealed flexible binding sites and conformations. We also describe structural dynamics studies of ABC transporters correlating conformational changes with various states. The study will shed light on strategies to overcome P-glycoprotein-mediated drug transport.

9:05 Engineering Scorpion Venom Peptides to Generate High Potent and Selective Therapeutics Targeting a Potassium Channel

Wilson Edwards, Ph.D., Principal Scientist, Biologics Research, Janssen R&D, LLC

Selectively blocking Kv1.3, a voltage-gated potassium channel involved in mediating active T cell responses, has been suggested as an approach for treating autoimmune diseases. However generating selective inhibitors remains a challenge. We present a series of highly selective and potent Kv1.3 blockers we identified by making an extensive chimeric peptide library of native peptide toxins, OsK1, a potent Kv blocker, and OdK2, a weak but specific Kv1.3 blocker.

9:35 Coffee Break in the Exhibit Hall with Poster Viewing


Different Types of Macrocyclics 

10:20 Selective Histone Deacetylase Inhibitors (HDACi) based on Cyclic Peptoids

Adrian CulfAdrian Culf, Ph.D., Research Scientist, Medicinal Chemistry, Atlantic Cancer Research Institute

Peptoids are peptide mimics, providing a large structural diversity of hydrolytically stable, membrane permeable molecules that are at the boundary between synthetic chemicals and biologics. These molecules are good candidates for exploring targets of medicinal interest. We present our work in automated peptoid synthesis (N-substituted glycine oligomer), macrocyclization for 9 to 15 atom rings, lead identification, molecular modelling, in vitro recombinant enzymatic and cellular activity of hydroxamate and thiol-capped cyclic peptoids.


10:50 Novel Natural Product-Based Macrocycles for Efficient Drug Discovery

Dietmar WolfDietmar Wolf, Ph.D., Executive Vice President, AnalytiCon Discovery, LLC

In addition to successful natural products as an inspirational source for new drugs, there is a high demand for diverse, suitable macrocyclic libraries with tractable chemistry. New concepts for the generation of macrocyclic compounds with superior diversity will be described including the integration of natural product building blocks into the modular synthesis of macrocycles.


11:20 2-CLIPS Peptides: Discovery and Optimization of a New Class of Biopharmaceuticals

Timmerman_PeterPeter Timmerman, Ph.D., CSO, Pepscan Therapeutics

2-CLIPS peptides constitute a unique class of constrained, bicyclic peptides that display affinities and selectivities comparable to those of antibodies. Their chemical synthesis is compatible with high-diversity screening in genetically-encoded libraries for identifying lead binders to a variety of different target proteins. Structural optimization via (non)-natural amino acid replacements using our high-sensitivity SIMPLIS-array platform improves their performance with orders of magnitude.

11:35 PANEL DISCUSSION: Library Design Strategies

Nicholas TerretModerator: Nicholas Terrett, Ph.D., CSO, Ensemble Therapeutics


Prabhat Arya, Ph.D., Professor, Chemistry and Chemical Biology, DRILS University of Hyderabad, India
Max Cummings, Ph.D., Principal Scientist, Discovery Sciences, Janssen

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

Peter Timmerman, Ph.D., CSO, Pepscan Therapeutics

  • How big and how diverse do macrocycle libraries need to be?
  • How can we best assess macrocycle diversity?
  • What is the focus in library design – target potency or drug-like properties?
  • What are the methods of maximizing cell permeability and oral bioavailability of macrocycles?
  • How do we position cyclic peptides and synthetic macrocycles to maximize success in drug discovery?

12:05 pm Walk and Talk Luncheon in the Exhibit Hall with Poster Viewing (last chance for viewing)


Case Studies: Targeting Intracellular Interactions 

1:25 Chairperson’s Remarks

Vincent Guerlavais, Ph.D., Distinguished Scientist, Aileron Therapeutics

1:30 Structure-Based Design of Macrocyclic Kinase Inhibitors leading to the Clinical Candidates Pacritinib, SB1317 & SB1578

AndersPoulsenAnders Poulsen, Ph.D., Senior Research Scientist, Experimental Therapeutics Centre, A*STAR

An HTS against Aurora A kinase revealed several promising pyrimidine-aniline leads. Macrocycle formation was proposed to achieve novelty and selectivity. In a kinase panel selected macrocycles were active on other kinase targets. Subsequently these compounds became leads in our CDK2/Flt3 and JAK2 projects. This presentation will concentrate on the structural biology and conformational properties of our macrocyclic kinase inhibitors as an explanation for their selectivity and SAR.

2:00 A Cyclic Peptide Hit Optimized to a Non-Peptidic Macrocycle that Targets an Intracellular PPI

Marc ThommenMarc Thommen, Ph.D., Head, Technology Platforms, Polyphor

We will describe a successful drug discovery case study of applying two complementary parts of our proprietary macrocycle platform that identifies and optimizes potent and selective modulators of intra- and extracellular
interactions (PPIs). In particular we highlight a successful case study for the structural transfer of a cyclic peptide hit to a non-peptidic macrocycle to address an intracellular PPI.

2:30 Macrocycle Analogs of Natural Products as Promising Antimalarial and Anti-Trypanosomal Agents: Synthesis and Biological Evaluation

Gloria SerraGloria Serra, Ph.D., Professor, Medicinal Chemistry, Organic Chemistry, Facultad de Química, Universidad de la República

Azolic and non-azolic cyclohexapetides analogs of antimalarial and/or antytripanosomal natural products were obtained in very good yields combining solid-phase peptide synthesis and solution synthesis. Seven of the synthesized macrocycles showed submicromolar EC50 against Plasmodium falciparum K1 and a high selectivity (SI > 125) for the parasite. In addition, five compounds displayed low micromolar EC50 against T. brucei brucei and good selectivity. Interestingly, several cyclohexapeptides exhibited satisfactory mutual anti-parasitic activities.

3:00 New Learnings about Macrocycles in Drug Discovery: Progress Towards Lead Series

Nicholas TerretNicholas Terrett, Ph.D., CSO, Ensemble Therapeutics Corp

Macrocycles are found widely in nature and several of these natural products are marketed as drugs with good drug-like properties. As it is difficult to readily generate analogs of natural products, the popularity of synthetic macrocycles for drug discovery has been steadily increasing. This presentation will update on recent findings on the druggabilty of macrocycles and will illustrate with examples of lead discovery programs from Ensemble.

3:30 Close of Conference

*Separate registration required; please click here for details.

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