Signaling through Rho GTPase pathway as viable drug target

Abstract

Signaling through the Rho family of small GTPases has been increasingly investigated for their involvement in a wide variety of diseases such as cardiovascular, pulmonary, and neurological disorders as well as cancer. Rho GTPases are a subfamily of the Ras superfamily proteins which play essential roles in a number of biological processes, especially in the regulation of cell shape change, cytokinesis, cell adhesion, and cell migration. Many of these processes demonstrate a common theme: the rapid and dynamic reorganization of actin cytoskeleton of which Rho signaling has now emerged as a major switch control. The involvement of dynamic changes of Rho GTPases in disease states underscores the need to produce effective inhibitors for their therapeutic applications. Fasudil and Y-27632, with many newer additions, are two classes of widely used chemical compounds that inhibit Rho kinase (ROCK), an important downstream effector of RhoA subfamily GTPases. These inhibitors have been successful in many preclinical studies, indicating the potential benefit of clinical Rho pathway inhibition. On the other hand, except for Rac1 inhibitor NSC23766, there are few effective inhibitors directly targeting Rho GTPases, likely due to the lack of optimal structural information on individual Rho-RhoGEF, Rho-RhoGAP, or Rho-RhoGDI interaction to achieve specificity. Recently, LM11A-31 and other derivatives of peptide mimetic ligands for p75 neurotrophin receptor (p75(NTR)) show promising effects upstream of Rho GTPase signaling in neuronal regeneration. CCG-1423, a chemical compound showing profiles of inhibiting downstream of RhoA, is a further attempt for the development of novel pharmacological tools to disrupt Rho signaling pathway in cancer. Because of a rapidly growing number of studies deciphering the role of the Rho proteins in many diseases, specific and potent pharmaceutical modulators of various steps of Rho GTPase signaling pathway are critically needed to target for therapeutic intervention in cardiovascular disease, neurological disorders, and cancer progression.

Fig. (1)

Schematic illustration of Rho GTPase signaling pathway. A. Receptor dependent and independent signaling through Rho GTPase pathway leading to actin reorganization. Numbered arrows indicate where the inhibitor targets are in the Rho GTPase signaling cascade: 1, Y27632, fasudil, and H-1152; 2, LM11A31; 3, statins; 4, NSC23766; 5, CCG-1423. B. Regulation of Rho GTPase activation and inactivation through Rho-GEFs, Rho-GAPs, and RhoGDIs.

Fig. (2)

Examples of Rho kinase (ROCK) inhibitors, fasudil, Y-27632, and H-1152.

Fig. (3)

LM11A compounds exhibiting activity upon p75^NTR binding: LM11A-7, 28, 24, and 31.

Fig. (4)

Selection of statin drugs capable of modulating Rho pathway signaling.

Fig. (5)

Novel inhibitors of RhoGTPase pathways, NSC23766, CCG-977, and CCG-1423.