Inhibitors of the ROCK serine/threonine kinases: key effectors of the RhoA small GTPase.

Aberrant activation of the RhoA small GTPase has been implicated in cancer and other human diseases. Therefore, inhibitors of RhoA may have important therapeutic value. However, similar to the Ras small GTPases, RhoA itself is not considered a tractable target and is currently considered to be "undruggable." While recent efforts suggest that direct inhibitors of the Ras oncoprotein may yet be developed, the most promising directions for anti-Ras inhibitors involve inhibitors of protein kinases that are activated downstream of Ras. By analogy, protein kinases activated downstream of RhoA may provide more attractive directions for the development of anti-RhoA inhibitors. Among the multitude of RhoA effectors, the ROCK serine/threonine kinases have emerged as attractive targets for anti-RhoA drug discovery. In this review, we summarize the current status of the development of small molecule inhibitors of ROCK.