Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423

We recently identified bis(amide) CCG-1423 (1) as a novel inhibitor of RhoA/C-mediated gene transcription that is capable of inhibiting invasion of PC-3 prostate cancer cells in a Matrigel model of metastasis. An initial structure–activity relationship study focusing on bioisosteric replacement of the amides and conformational restriction identified two compounds, 4g and 8, with improved selectivity for inhibition of RhoA/C-mediated gene transcription and attenuated cytotoxicity relative to 1. Both compounds were also capable of inhibiting cell invasion with equal efficacy to 1 but with less attendant cytotoxicity.

Conformational restriction and bioisosteric amide replacement were used to generate novel analogs of the Rho-transcriptional pathway inhibitor CCG-1423. Two compounds were found with significantly improved selectivity for inhibition of PC-3 cancer cell invasion versus cytotoxicity.Figure optionsDownload as PowerPoint slide