Optimization of novel nipecotic bis(amide) inhibitors of the Rho/MKL1/SRF transcriptional pathway as potential anti-metastasis agents

CCG-1423 (1) is a novel inhibitor targeting Rho/MKL1/SRF-mediated gene transcription, shown to suppress the invasion of PC-3 prostate cancer cells in a Matrigel-based metastasis model. Building on this foundation, we recently designed and synthesized conformationally restricted analogs, such as compound 2, which demonstrated improved selectivity for inhibiting cell invasion over inducing acute cytotoxicity. In the current study, we explored aromatic substitutions to optimize physicochemical properties (e.g., ClogP, molecular weight) for future in vivo efficacy testing. This effort led to the identification of two new compounds with significantly reduced cytotoxicity and a fourfold increase in potency compared to compound 2 for inhibiting PC-3 cell migration in a scratch wound assay. Notably, one compound, 8a (CCG-203971, IC50 = 4.2 μM), was well tolerated in mice at 100 mg/kg/day administered intraperitoneally for five days and achieved plasma concentrations exceeding its migration IC50 for up to three hours.