Seminar title: Stapled Peptide Drugs: Nature’s α−Helix to Breakthrough Medicines

Abstract:

Nature’s α-helix is a key structural motif involved in protein function and protein-protein interactions. Intracellular pathways leverage **helical interfaces in extraordinary ways to modulate many biological functions. This seminar will highlight the structure-based design, medicinal chemistry, biochemistry, cell biology and pharmacology of a novel stapled **helical peptide (ATSP-7041) that is a dual inhibitor of MDM2/MDMX and reactivates p53-dependent pathway in multiple cancer cell lines in vitro and in vivo. ATSP-7041 binds both MDM2 and MDMX with nanomolar affinities, exhibits sub-micromolar cellular activity in cancer cell lines in the presence of serum, and demonstrates evidence of specific on-target mechanism in vitro by gene expression profiling. A high resolution X-ray crystal structure of ATSP-7041 bound to MDMX revealed its molecular interactions to the target protein, including multiple contacts between both key pharmacophoric amino acid side chains and the hydrocarbon staple moiety. ATSP-7041 is the first example of a negatively charged, amphipathic stapled a-helical peptide having potent efficacy in vitro and In vivo. A series of ATSP-7041 analogs provide insight to the biophysical properties and structure-activity relationships that underscore its lead optimization. This work has been recently published in the Proceedings of the National Academy of Sciences USA.

Tomi Sawyer, Ph.D.
Entrepreneurial Drug Hunter
Adjunct Professor, Department of Chemistry and Department of Biochemistry & Molecular Biology, University of Massachusetts; Department of Cancer Biology, University of Massachusetts Medical School
Past-Founding Chief Scientific Officer & Senior Vice-President, Drug Discovery and Innovative Technologies, Aileron Therapeutics