Toward the development of a potent and selective organoruthenium mammalian sterile 20 kinase inhibitor

J Med Chem. 2009 Mar 26;52(6):1602-11. doi: 10.1021/jm8005806.

Abstract

Mammalian sterile 20 (MST1) kinase, a member of the sterile 20 (Ste-20) family of proteins, is a proapoptotic cytosolic kinase that plays an important role in the cellular response to oxidative stress. In this study, we report on the development of a potent and selective MST1 kinase inhibitor based on a ruthenium half-sandwich scaffold. We show that the enantiopure organoruthenium inhibitor, 9E1, has an IC50 value of 45 nM for MST1 and a greater than 25-fold inhibitor selectivity over the related Ste-20 kinases, p21 activated kinase 1 (PAK1), and p21 activated kinase 4 (PAK4) and an almost 10-fold selectivity over the related thousand-and-one amino acids kinase 2 (TAO2). Compound 9E1 also displays a promising selectivity profile against unrelated protein kinases; however, the proto-oncogene serine/threonine protein kinase PIM1 (PIM-1) and glycogen synthase kinase 3 (GSK-3beta) are inhibited with IC50 values in the low nanomolar range. We also show that 9E1 can inhibit MST1 function in cells. A cocrystal structure of a related compound with PIM-1 and a homology model with MST1 reveals the binding mode of this scaffold to MST1 and provides a starting point for the development of improved MST1 kinase inhibitors for possible therapeutic application.

Publication types

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

MeSH terms

  • Cell Membrane Permeability
  • Crystallography, X-Ray
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Ruthenium Compounds / chemistry*
  • Ruthenium Compounds / metabolism
  • Ruthenium Compounds / pharmacology*

Substances

  • Histones
  • Ruthenium Compounds
  • STK4 protein, human
  • Protein-Serine-Threonine Kinases