CCG-1423 inhibits RhoA/C-mediated gene transcription and the invasion of rho-overexpressing cell lines.
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Rho GTPases are molecular switches that regulate many essential cellular processes, including actin dynamics, gene transcription, cell-cycle progression and cell adhesion[3]. Rho-kinase has pleiotropic functions including the regulation of cellular contraction, motility, morphology, polarity, cell division, and gene expression[4]. CCG-1423 is 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. CCG-1423 selectively inhibited spontaneous PC-3 prostate cancer cell invasion through a Matrigel matrix in vitro, but not the Gαi-dependent LPA-stimulated SKOV-3 ovarian cancer cell invasion in vitro. At 100 μM, nearly complete inhibition of invasion was achieved with a lesser degree of toxicity than that induced by CCG-1423 at 10 μM[5]. Pharmacological SRF inhibition by CCG-1423 reduced nuclear MKL1 and improved glucose uptake and tolerance in insulin-resistant mice in vivo[6]. SRF binds to this site in vivo and the SRF inhibitor CCG-1423 completely blocks STARS proximal reporter activity in H9c2 cells[7]. Pharmacological MKL-inhibition with CCG-1423 significantly inhibited CCN1 promoter activity as well as mRNA and protein expression[8].
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