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

Oncogene volume 33, pages 550–555 (2014)Cite this article

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Abstract

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; IC50 values of 397 nM (ROCK1) and 349 nM (ROCK2)) and RKI-11 (weak/inactive; IC50 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 ½. 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.

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Acknowledgements

We would like to thank Nan Sun (Moffitt Cancer Center) and the following Moffitt Cancer Center core facilities: the Chemical Biology Core, the Analytical Microscopy Core and Comparative Medicine Core facility. This work was supported by NCI grant U19 CA 067771.

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Authors and Affiliations

  1. Drug Discovery Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

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

  2. Departments of Oncologic Sciences and Molecular Medicine, University of South Florida, Tampa, FL, USA

    S M Sebti

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Correspondence to S M Sebti.

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Patel, R., Liu, Y., Wang, B. et al. Identification of novel ROCK inhibitors with anti-migratory and anti-invasive activities. Oncogene 33, 550–555 (2014). https://doi.org/10.1038/onc.2012.634

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