Reactivation of suppressed RhoB is a critical step for the inhibition of cancer cell growth. The exact mechanism is still obscure, although some RhoB modulators were found which exhibited an anticancer effect. To this end, a novel RhoB modulator, G02, has been identified and evaluated. In the efforts to explore new chemical entities for novel RhoB modulators, we have identified a number of potent and selective antitumor agents for gastric and prostate cancer with excellent in vitro and in vivo profiles. Although analogs related to compound G02 had good cancer cell growth inhibition activities, poor in vivo tumor regression activities were observed due to the low plasma exposure. Therefore, the further optimization of various analogues was performed by an intravenous administration. Finally A665 displayed excellent inhibitory activities on prostate and gastric cancer cells and no sign of toxicity. In this presentation, we will reveal structure-activity relationship (SAR) study, in vitro and in vivo data, and syntheses of a number of these novel RhoB modulators.

Design, synthesis, and biological evaluation of novel RhoB modulators as antitumor agents

239th National Meeting (2010)

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