Structure-Activity Relationship Studies of the Cyclic Depsipeptide Natural Product YM-254890, Targeting the Gq Protein

ChemMedChem. 2017 Jun 7;12(11):830-834. doi: 10.1002/cmdc.201700155. Epub 2017 May 16.

Abstract

Extracellular signals perceived by G protein-coupled receptors are transmitted via G proteins, and subsequent intracellular signaling cascades result in a plethora of physiological responses. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known compounds that specifically inhibit signaling mediated by the Gq subfamily. In this study we exploit a newly developed synthetic strategy for this compound class in the design, synthesis, and pharmacological evaluation of eight new analogues of YM-254890. These structure-activity relationship studies led to the discovery of three new analogues, YM-13, YM-14, and YM-18, which displayed potent and selective Gq inhibitory activity. This provides pertinent information for the understanding of the Gq inhibitory mechanism by this class of compounds and importantly provides a pathway for the development of labeled YM-254890 analogues.

Keywords: G protein-coupled receptors; YM-254890; biological activity; peptide synthesis; structure-activity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Depsipeptides / chemistry*
  • Depsipeptides / pharmacology*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / antagonists & inhibitors*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / chemistry
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Humans
  • Molecular Targeted Therapy
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / pharmacology*
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism
  • Sequence Analysis, Protein
  • Structure-Activity Relationship

Substances

  • Depsipeptides
  • Peptides, Cyclic
  • Receptors, G-Protein-Coupled
  • YM-254890
  • GTP-Binding Protein alpha Subunits, Gq-G11