Chemical Features Important for Activity in a Class of Inhibitors Targeting the Wip1 Flap Subdomain

ChemMedChem. 2018 May 8;13(9):894-901. doi: 10.1002/cmdc.201700779. Epub 2018 Apr 6.

Abstract

The wild-type p53 induced phosphatase 1, Wip1 (PP2Cδ), is a protein phosphatase 2C (PP2C) family serine/threonine phosphatase that negatively regulates the function of the tumor suppressor p53 and several of its positive regulators such as ATM, Chk1, Chk2, Mdm2, and p38 MAPK. Wip1 dephosphorylates and inactivates its protein targets, which are critical for cellular stress responses. Additionally, Wip1 is frequently amplified and overexpressed in several human cancer types. Because of its negative role in regulating the function of tumor suppressor proteins, Wip1 has been identified as a potential therapeutic target in various types of cancers. Based on a recently reported Wip1 inhibitor (G-1), we performed an extensive structure-activity relationship (SAR) analysis. This led us to interesting findings in SAR trends and to the discovery of new chemical analogues with good specificity and bioavailability.

Keywords: ELISA; Wip1; enzyme kinetics; inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • MCF-7 Cells
  • Protein Phosphatase 2C / antagonists & inhibitors*
  • Protein Phosphatase 2C / metabolism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Enzyme Inhibitors
  • PPM1D protein, human
  • Protein Phosphatase 2C