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Characterization of EHop-016, novel small molecule inhibitor of Rac GTPase.
Montalvo-Ortiz, Brenda L; Castillo-Pichardo, Linette; Hernández, Eliud; Humphries-Bickley, Tessa; De la Mota-Peynado, Alina; Cubano, Luis A; Vlaar, Cornelis P; Dharmawardhane, Suranganie.
Affiliation
  • Montalvo-Ortiz BL; Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico.
J Biol Chem ; 287(16): 13228-38, 2012 Apr 13.
Article in En | MEDLINE | ID: mdl-22383527
The Rho GTPase Rac regulates actin cytoskeleton reorganization to form cell surface extensions (lamellipodia) required for cell migration/invasion during cancer metastasis. Rac hyperactivation and overexpression are associated with aggressive cancers; thus, interference of the interaction of Rac with its direct upstream activators, guanine nucleotide exchange factors (GEFs), is a viable strategy for inhibiting Rac activity. We synthesized EHop-016, a novel inhibitor of Rac activity, based on the structure of the established Rac/Rac GEF inhibitor NSC23766. Herein, we demonstrate that EHop-016 inhibits Rac activity in the MDA-MB-435 metastatic cancer cells that overexpress Rac and exhibits high endogenous Rac activity. The IC(50) of 1.1 µM for Rac inhibition by EHop-016 is ∼100-fold lower than for NSC23766. EHop-016 is specific for Rac1 and Rac3 at concentrations of ≤5 µM. At higher concentrations, EHop-016 inhibits the close homolog Cdc42. In MDA-MB-435 cells that demonstrate high active levels of the Rac GEF Vav2, EHop-016 inhibits the association of Vav2 with a nucleotide-free Rac1(G15A), which has a high affinity for activated GEFs. EHop-016 also inhibits the Rac activity of MDA-MB-231 metastatic breast cancer cells and reduces Rac-directed lamellipodia formation in both cell lines. EHop-016 decreases Rac downstream effects of PAK1 (p21-activated kinase 1) activity and directed migration of metastatic cancer cells. Moreover, at effective concentrations (<5 µM), EHop-016 does not affect the viability of transformed mammary epithelial cells (MCF-10A) and reduces viability of MDA-MB-435 cells by only 20%. Therefore, EHop-016 holds promise as a targeted therapeutic agent for the treatment of metastatic cancers with high Rac activity.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidines / Breast Neoplasms / Carbazoles / Rac1 GTP-Binding Protein / Enzyme Inhibitors Type of study: Prognostic_studies Limits: Female / Humans Language: En Journal: J Biol Chem Year: 2012 Document type: Article Affiliation country: Puerto Rico Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidines / Breast Neoplasms / Carbazoles / Rac1 GTP-Binding Protein / Enzyme Inhibitors Type of study: Prognostic_studies Limits: Female / Humans Language: En Journal: J Biol Chem Year: 2012 Document type: Article Affiliation country: Puerto Rico Country of publication: United States