An irreversible inhibitor of peptidyl-prolyl cis/trans isomerase Pin1 and evaluation of cytotoxicity

Bioorg Med Chem Lett. 2019 Feb 1;29(3):353-356. doi: 10.1016/j.bmcl.2018.12.044. Epub 2018 Dec 19.

Abstract

Pin1 (protein interacting with never in mitosis A-1) is a member of the peptidyl prolyl isomerase (PPIase) family, and catalyzes cis-trans isomerization of pThr/Ser-Pro amide bonds. Because Pin1 is overexpressed in various cancer cell lines and promotes cell growth, it is considered a target for anticancer agents. Here, we designed and synthesized a covalently binding Pin1 inhibitor (S)-2 to target Pin1's active site. This compound inhibited Pin1 in protease-coupled assay, and formed a covalent bond with Cys113 of Pin1, as determined by ESI-MS. The acetoxymethyl ester of (S)-2, i.e., 6, suppressed cyclin D1 expression in human prostate cancer PC-3 cells, and exhibited cytotoxicity. Pin1-knockdown experiments indicated that a target for the cytotoxicity of 6 is Pin1.

Keywords: Covalent bond; Cysteine; Irreversible inhibition; Michael acceptor; Peptidyl prolyl isomerase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HCT116 Cells
  • Humans
  • Molecular Structure
  • NIMA-Interacting Peptidylprolyl Isomerase / antagonists & inhibitors*
  • NIMA-Interacting Peptidylprolyl Isomerase / metabolism
  • PC-3 Cells
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • NIMA-Interacting Peptidylprolyl Isomerase
  • PIN1 protein, human