A novel selective multikinase inhibitor of ROCK and MRCK effectively blocks cancer cell migration and invasion

Cancer Lett. 2014 Nov 28;354(2):299-310. doi: 10.1016/j.canlet.2014.08.032. Epub 2014 Aug 27.

Abstract

Two structurally related protein kinase families, the Rho kinases (ROCK) and the myotonic dystrophy kinase-related Cdc42-binding kinases (MRCK) are required for migration and invasion of cancer cells. We hypothesized that simultaneous targeting of these two kinase families might represent a novel therapeutic strategy to block the migration and invasion of metastatic cancers. To this end, we developed DJ4 as a novel small molecule inhibitor of these kinases. DJ4 potently inhibited activities of ROCK and MRCK in an ATP competitive manner. In cellular functional assays, DJ4 treatment significantly blocked stress fiber formation and inhibited migration and invasion of multiple cancer cell lines in a concentration dependent manner. Our results strongly indicate that DJ4 may be further developed as a novel anti-metastatic chemotherapeutic agent for multiple cancers.

Keywords: Cancer; MRCK; Migration; Multikinase inhibitor; ROCK; Stress fibers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Humans
  • Myotonin-Protein Kinase / antagonists & inhibitors*
  • Neoplasm Invasiveness
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Thiazolidines / pharmacology*
  • rho-Associated Kinases / antagonists & inhibitors*

Substances

  • 2-5-(1H-pyrrolo(2,3-b)pyridine-3-ylmethylene)-1,3-thiazol-4(5H)-one
  • Protein Kinase Inhibitors
  • Thiazolidines
  • CDC42BPA protein, human
  • CDC42BPB protein, human
  • Myotonin-Protein Kinase
  • ROCK1 protein, human
  • rho-Associated Kinases