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Rational design and applications of a Rac GTPase-specific small molecule inhibitor

All Rights Reserved. Rational design and applications of a Rac GTPase-specific small molecule inhibitor. Akbar, Huzoor; Cancelas, Jose; Williams, David A.; Zheng, Jie; Zheng, Yi (Division of Experimental Hematology, Childrens Hospital Research Foundation, Cincinnati, OH, USA). Methods in Enzymology, 406(Regulators and Effectors of Small GTPases: Rho Family), 554-565 (English) 2006 Elsevier.Chemicals with cas numbers 733767-34-5 and 9002-04-4 also play role. CODEN: MENZAU. ISSN: 0076-6879. DOCUMENT TYPE: Journal; General Review CA Section: 1 (Pharmacology) A review. Rac GTPases are involved in the regulation of multiple cell functions and have been implicated in the pathol. of certain human diseases. Dominant neg. mutants of Rac have been the tool of choice in studying Rac function in cells. Given the difficulty of introducing high concns. of the Rac mutants into primary cells and nonspecific effects of the mutants on Rho guanine nucleotide exchange factor (GEF) activities, it is desirable to develop small mol. inhibitors that could specifically inhibit Rac activities. Here the authors describe the rational design, characterization, and applications of a first-generation Rac-specific small mol. inhibitor. On the basis of the structure-function information of Rac interaction with GEFs, in a computer-based virtual screening the authors have identified NSC23766, a highly sol. and membrane permeable compd., as a specific inhibitor of a subset of GEF binding to Rac and, therefore, Rac activation by these GEFs. In fibroblast cells, NSC23766 inhibited Rac1 GTP-loading without affecting Cdc42 or RhoA activity and suppressed cell proliferation induced by a Rac GEF Tiam1. It has little effect on cell growth induced by a constitutively active Rac1 mutant. In addn., NSC23766 inhibited: the anchorage-independent growth and invasion phenotypes of human prostate cancer PC-3 cells; Rac activation and Rac-dependent aggregation of platelets stimulated by thrombin; and Rac1 and Rac2 activities of hematopoietic stem/progenitor cells and induced their mobilization from mouse bone marrow to peripheral blood. Thus, NSC23766 is a lead small mol. inhibitor of Rac activity and could be useful for studying Rac-mediated cellular functions and for modulating pathol. conditions in which Rac-deregulation may play a role. .