Abstract LB-305: Novel Rac1-GEF inhibitors as anticancer agents for aggressive tumors.

Abstract Small GTPases of the Rho family, including Rac1, regulate fundamental cellular processes like actin cytoskeleton reorganization, cell migration and cell cycle progression. Rac1 has been associated with transformation, tumor progression and tumor cell migration in different type of cancers, including aggressive breast cancer and glioma. These proteins cycle between an active, GTP-bound state and an inactive, GDP-bound state. This cycle is highly regulated by many regulatory proteins, including activators such as guanine nucleotide exchange factors (GEFs). We searched for Rac1 inhibitors able to interfere Rac1-GEF interaction using a docking-based virtual library screening approach. We selected ZINC69391 compound. This small-molecule was able to interfere Rac-Tiam1 and Rac-DOCK180 interaction in vitro and reduced Rac1-GTP intracellular levels but had no effect on the closely related Cdc42 GTPase. ZINC69391 also affected the activation of Pak1, one important Rac1 effector. This compound reduced cell migration, inhibited cell proliferation and arrested cell cycle progression in breast cancer cells and glioma cells. We also evaluated this compound in vivo and ZINC69391 was able to reduce 60% lung colonization in a breast cancer experimental metastasis model. We further evaluated novel analogs looking for more potent and specific Rac1 inhibitors. We synthesized a group of novel disubstituted guanidines and we screened these analogs in vitro. One of them, 1A-116 analog, showed to be more potent than the parental compound, reducing cancer cell proliferation and Rac1 activation at the low micromolar range. These data further confirm Rac1 GTPase as a valuable molecular target for anti-cancer therapies and drug development in breast cancer and glioma, where Rac1 presents a relevant role. Citation Format: Georgina A. Cardama, Nazareno Gonzalez, Maria Julieta Comin, Adrian G. Turjanski, Daniel Fernando Alonso, Daniel Eduardo Gomez, Pablo Lorenzano Menna. Novel Rac1-GEF inhibitors as anticancer agents for aggressive tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-305. doi:10.1158/1538-7445.AM2013-LB-305