Identification of novel ROCK inhibitors with anti-migratory and anti-invasive activities

R. A. Patel, Y. Liu, B. Wang, R. Li, S. M. Sebti

Research output: Contribution to journalArticle

41 Scopus citations


ROCK1 and ROCK2 mediate important processes such as cell migration, invasion and metastasis, making them good targets for the development of antitumor agents. Recently, using a fragment-based approach and X-ray crystallography, we reported on the design and synthesis of novel Rho-kinase inhibitors (RKIs). Here, we selected a pair of RKIs, the closely related structural analogs RKI-18 (potent; IC 50 values of 397 nM (ROCK1) and 349 nM (ROCK2)) and RKI-11 (weak/inactive; IC 50 values of 38 μM (ROCK1) and 45 μM (ROCK2)), as chemical probes and determined their effects on cytoskeleton organization, signaling, apoptosis, anchorage-dependent and independent growth, migration and invasion. RKI-18 but not RKI-11 suppresses potently the phosphorylation of the ROCK substrate myosin light chain 2 (MLC2) in intact human breast, lung, colon and prostate cancer cells. Furthermore, RKI-18 is highly selective at decreasing the levels of P-MLC2 over those of P-Akt, P-S6 and P-Erk. RKI-18 suppresses ROCK-mediated actin fiber formation, following stimulation with LPA as well as p21-activated kinase (PAK)-mediated lamellipodia and filopodia formation following bradykinin or PDGF stimulation. Furthermore, RKI-18 but not RKI-11 inhibits migration, invasion and anchorage-independent growth of human breast cancer cells. The fact that the active ROCK inhibitor RKI-18, but not the inactive closely related structural analog RKI-11 is effective at suppressing malignant transformation suggests that inhibition of ROCK with RKI-18 results in preventing migration, invasion and anchorage-independent growth. The potential of this class of RKIs as anti-tumor agents warrants further advanced preclinical studies.

Original languageEnglish (US)
Pages (from-to)550-555
Number of pages6
Issue number5
StatePublished - Jan 30 2014


  • MLC-2
  • RKI-18
  • ROCK1
  • ROCK2
  • invasion
  • migration

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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