Producción CyT
Medicina Buenos Aires - Preclinical antitumor efficacy and pharmacokinetics of the Rac1 inhibitor compound 1A-116: comparison of different administration routes
Congreso
Autoría:
Cardama, Georgina A. ; Nazareno Gonzalez ; Gomez, Daniel E. ; Demarco, Ignacio A. ; Ortega H. ; GARONA, JUAN ; Alonso, Daniel F.Fecha:
2022Editorial y Lugar de Edición:
Fundación Revista MedicinaResumen *
Rac1 is a key mediator of different relevant cellular functions, such as proliferation, migration and invasion. Aberrant Rac1 signaling is associated with progression in several tumor types, including breast cancer. Previously, our team developed the antitumor compound 1A-116, a small molecule Rac1 inhibitor, using a rational design approach. We have shown that 1A-116 is able to interact with Trp56, a key Rac1 residue involved in its activation by different guanine nucleotide exchange factors. Such interaction abrogates Rac1 signaling, thus generating antitumor effects in vitro and in vivo. These previous evidences supported further preclinical development of 1A-116. The aim of this work was to evaluate oral, subcutaneous (SC), intravenous (IV) and intraperitoneal (IP) administration routes of an aqueous formulation of 1A-116. We first analyzed drug effects in Balb/c mice implanted in the subcutis with F3II tumors (2 x 105 cells/mouse), an aggressive hormone-independent mammary carcinoma model. Daily IP treatment with 10 mg/kg 1A-116 significantly reduced in vivo tumor growth and similar results were observed when mice were treated once a week with 1 mg/kg IV. We also evaluated drug effects on experimental lung colonization by F3II cells injected via tail vein (105 cells/mouse). IP administration showed a significant reduction in the number of metastatic lung nodules, but oral and SC 1A-116 administration had no effect. The pharmacokinetic study showed that 1A-116 has a good distribution after IP or IV administration (peak plasma concentrations 0.7-1.4 µg/ml), and poor oral bioavailability with this aqueous formulation. Importantly, 1A-116 showed a favorable acute toxicology profile in mice, with maximum tolerated doses of 80 mg/kg and 8 mg/kg for IP and IV routes, respectively. Our preclinical experiments highlight 1A-116 compound as a promising candidate for the treatment of aggressive tumors with aberrant Rac1 signaling. Información suministrada por el agente en SIGEVAPalabras Clave
1A-116 COMPOUNDANTICANCERRAC-1PK/PD