As a small GTPase, Rac1 switches between active and inactive states at various subcellular locations that include the plasma membrane, nucleus and mitochondria. Once activated, Rac1 interacts with a range of effectors that then mediate various biological functions[1]. 1A-116 is a specific Rac1 inhibitor[2]. 1A-116 shows lesser effect on MCF7::pcDNA.3 cells than on MCF7::C1199 cells. 1A-116 treatment decreases phospho-PAK1 levels in a time-dependent manner. The presence of 1A-116 reverts the PAK1 phosphorylation induced by 4-hydroxytamoxifen (Tam). The presence of 1A-116 also effectively reverts Rac1-PAK1-mediated estrogen receptor (ER) phosphorylation at Ser305[2]. 1A-116 shows a significant increase in antiproliferative activity on F3II cells, showing an IC50 value of 4 µM. A-116 also dramatically impaired Rac1 activation at low micromolar range (1 µM)[3]. Daily treatment of mice with compound 1A-116 at 3mg/kg reduced about 60% the formation of total metastatic lung colonies. A significant antitumor activity is obtained for macronodules (more than 1 mm in diameter) by treatment with 1A-116 in this highly aggressive breast cancer model. The treatment with 1A-116 reduced the total lung weight compare to the control group, leading to a total weight similar to the average pulmonary weight of Balb/c mice[3].
作用机制
Several hydrogen bonds are established between the guanidine nitrogen atoms and residues Asp57 and Ser71. Moreover, pi-stacking interactions are observed between the methylated aromatic ring of the 1A-116 and the aromatic ring of Trp56.
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