Design and Synthesis of Rac1 inhibitors as Potential Antitumor Agents.

MATIAS CIARLANTINI; NAZARENO GONZALEZ; DEFELIPE L.; LUCIA GANDOLFI DONADÍO; TURJANSKI, A; PABLO LORENZANO MENNA; MARIA J. COMIN

Simposio; 7th Brazilian Symposium on Medicinal Chemistry; 2014

Rho GTPases are a family of small GTP-binding proteins involved in cell cytoskeleton organization, migration, transcription, and proliferation. They act as molecular switches that cycle between an inactive GDP-bound and an active GTP-bound form. Guanine nucleotide exchange factors (GEFs) highly regulates this process. The active GTP-bound state binds preferentially to downstream effectors proteins and actively transduces signals.1 The aberrant activation of Rac1, one of the most studied Rho GTPases, is involved in tumor progression, invasion and metastasis and it is considered a promising target for novel anticancer drug development.2 We and others have been working on the development of new protein-protein interaction inhibitors (Rac1-GEF). Through a virtual screening we have identified hit compound ZINC69391 (1) that was further optimized to 1A-116 (2) that showed greater in vivo potency in cell-base antiproliferative assays and impaired metastatic lung colonization in a syngenic animal model among others studies.3