2013 Archived Content


Constrained Peptides and Macrocyclics Drug Discovery

Novel Peptide Therapeutics

April 16-17, 2013

Peptide therapeutics are making a come-back due to chemical advances that have created new sorts of peptide-based structures that not only combine the best of both, small molecule and antibody drug candidates, but also have unique advantages. Like small molecule compounds, these new peptide derivatives are small enough (under 5 kilodaltons) to be developed into oral therapeutics, but they have the advantage of being large enough to disrupt protein-protein interactions, making them more useful against intracellular targets. This new class of peptides also has the specificity of larger proteins, such as monoclonal antibodies, but without the stability issues. This day and a half meeting will explore the chemistry and drug development advances behind this promising middle space of compounds that are slightly larger than 'small molecules' but smaller than 'biologics'.

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Scientific Advisor: Dinesh Patel, Ph.D., CEO, Protagonist Therapeutics

7:00 am Registration and Morning Coffee

Creating Constrained Peptides 

8:00 Chairperson’s Opening Remarks

Dinesh Patel, Ph.D., CEO, Protagonist Therapeutics


A Renaissance of Peptide Drug Discovery: Transforming Nature’s alpha-Helix into Breakthrough Medicines

Tomi Sawyer, Ph.D., CSO, Aileron Therapeutics

A renaissance of peptide drug discovery is leveraging innovative approaches to create constrained and macrocyclic analogs as novel modulators of extracellular and intracellular targets as well as tackle complex disease mechanisms. As a case study, advancements in stapled peptide technology to transform Nature’s alpha-helix into breakthrough medicines will be presented.

8:50 Engineered Knottin Peptides: A New Class of Tumor Targeting and Molecular Imaging Agents

Jennifer Cochran, Ph.D., Associate Professor, Bioengineering, Stanford University

Cystine knot peptides (also known as knottins) are constrained by three interwoven disulfide bonds that confer high chemical, thermal, and proteolytic stability ideal for in vivo applications. We used rational and combinatorial methods to engineer knottin peptides that bind with low to sub-nanomolar affinity to tumor-associated receptors. In this talk, the evaluation of engineered knottin peptides in preclinical tumor models and their promise as diagnostic and therapeutic agents will be discussed.

9:20 Conformational Constraints in Opioid Peptides

Steven Ballet, Ph.D., Research Group of Organic Chemistry, Departments of Bio-Engineering Sciences and Chemistry, Vrije Universiteit Brussel

9:50 Networking Coffee Break

10:15 Oral Disulfide Rich Peptide (DRP) Therapeutics

Dinesh V. Patel, Ph.D., President and CEO, Protagonist Therapeutics

Peptides as ‘orally stable entities’ is admittedly a conflicting concept.  Protagonist is focused on disulfide rich peptides (DRPs), a specific sub-class of peptides with inherently better stability than normal peptides.   Examples and approaches towards transforming DRPs as orally stable therapeutic agents will be described.

10:45 EKO: A Method to Discover Small Molecules to Perturb Protein-Protein Interactions

Kevin Burgess, Ph.D., Professor, Department of Chemistry, Texas A&M University

Very recently, our group has devised a new approach to the problem of finding molecules that perturb specific PPIs; we call this Exploring Key Orientations. It involves defining a set of chemotypes for molecules that are ideally suited to this function (two examples are shown below), then matching their preferred conformations with structural features of PPI-interface regions on a massive scale. Significantly, it is a chemistry-centered method where small molecule design takes priority over bioassay considerations.

11:15 The Development of Linaclotide for the Treatment of Chronic Functional Gastrointestinal Disorders

Angelika Fretzen, Ph.D., VP of Pharmaceutical Chemistry and Development, Ironwood Pharmaceuticals

11:45 Lunch on Your Own


Macrocyclic-Based Drug Candidates 

1:25 Chairperson’s Remarks

Julio Camarero, Ph.D., Associate Professor, Pharmacology and Chemistry, University of Southern California

1:30 SOM230: A New Therapeutic Modality for Cushing’s Disease

Ian Lewis, Ph.D., Research Chemist, Global Discovery Chemistry, Novartis

SOM230 has recently shown promise as the first effective pituitary directed medical treatment for Cushing’s disease. Indeed, the multiple high affinity binding of SOM230 to somatostatin receptor subtypes enables much more effective inhibition of ACTH release in vitro and in vivo. Recent clinical studies involving treatment of Cushing’s disease with SOM230 have demonstrated that SOM230 produced a decrease in urinary free cortisol (UFC) levels in 76% of patients during 15 days, with direct effects on ACTH release, establishing a new therapeutic modality for Cushing’s disease.

2:00 Discovery of Stereochemically Complex Macrocyclic Hsp90 Inhibitors

Christoph Zapf, Ph.D., Principal Scientist, Worldwide Medicinal Chemistry, Pfizer

We wish to disclose the design and synthesis of a series of stereochemically complex, rule-of-five compliant small molecule macrocycles that were fine-tuned to be metabolically stable and devoid of hERG activity. The compounds showed impressive biomarker activity 24 hours post dosing in different cell lines. When studied in a lung cancer xenograft model, the macrocycles demonstrated prolonged exposure in tumors and significant tumor size reduction.

2:30 Discovery of TZP-102, a Macrocycle-Based Oral Ghrelin Receptor Agonist and GI Prokinetic Agent for the Treatment of Diabetic Gastroparesis

Helmut Thomas, Ph.D., Senior Vice President, Research and Preclinical Development, Tranzyme Pharma

3:00 Sponsored Presentation (Opportunity Available)

3:15 Refreshment Break in the Exhibit Hall with Poster Viewing

4:00 Macrocycles for Drug Discovery - Identification of Small Molecule Synthetic Macrocycle Antagonists of Human IL17A

Nick Terrett, Ph.D., CSO, Ensemble Therapeutics Corp.

Ensemble Therapeutics has developed a DNA-programmed chemistry platform for the rapid synthesis and screening of macrocycles (EnsemblinsTM). Using this platform, small molecule macrocyclic compounds have been discovered that are nanomolar inhibitors of the interaction of the IL17A cytokine with its receptor. These compounds are anti-inflammatory in IL17-dependent animal inflammatory models and optimized for oral bioavailability.

Jack Szostak» 4:30 PLENARY KEYNOTE

mRNA Display: From Basic Principles to Macrocycle Drug Discovery

Jack W. Szostak, Ph.D., Investigator, Howard Hughes Medical Institute; Professor of Genetics, Harvard Medical School; Nobel Laureate - Biography 

The covalent attachment of a nascent protein or peptide to its own mRNA allows the in vitro selection of functional proteins and peptides from large libraries. This approach has recently been extended to the in vitro selection of highly modified cyclic peptides, a promising class of therapeutic agents.

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

6:30 End of Day

7:00 - 10:00 Complimentary Shuttle Bus Roundtrips to Downtown San Diego, Courtesy of Hilton San Diego Resort & Spa

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