Rho GTPases play a key role in the regulation of multiple essential cellular processes, including actin dynamics, gene
transcription and cell cycle progression. Aberrant activation of Rac1, a member of Rho family of small GTPases, is associated with
tumorigenesis, cancer progression, invasion and metastasis. Particularly, Rac1 is overexpressed and hyperactivated in highly aggressive
breast cancer. Thus, Rac1 appears to be a promising and relevant target for the development of novel anticancer drugs. We identified the
novel Rac1 inhibitor ZINC69391 through a docking-based virtual library screening targeting Rac1 activation by GEFs. This compound
was able to block Rac1 interaction with its GEF Tiam1, prevented EGF-induced Rac1 activation and inhibited cell proliferation, cell
migration and cell cycle progression in highly aggressive breast cancer cell lines. Moreover, ZINC69391 showed an in vivo antimetastatic
effect in a syngeneic animal model. We further developed the novel analog 1A-116 by rational design and showed to be specific and
more potent than the parental compound in vitro and interfered Rac1-P-Rex1 interaction. We also showed an enhanced in vivo potency of
1A-116 analog. These results show that we have developed novel Rac1 inhibitors that may be used as a novel anticancer therapy.
Breast cancer, docking, Rac1 inhibitor, rational design, virtual screening.
Laboratorio de Oncología Molecular, Universidad Nacional de Quilmes. Roque Saenz Pena 352, Bernal B1876BXD Buenos Aires, Argentina.