Article

CCG-1423: A small-molecule inhibitor of RhoA transcriptional signaling

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
Molecular Cancer Therapeutics (Impact Factor: 6.11). 08/2007; 6(8):2249-60. DOI: 10.1158/1535-7163.MCT-06-0782
Source: PubMed

ABSTRACT Lysophosphatidic acid receptors stimulate a Galpha(12/13)/RhoA-dependent gene transcription program involving the serum response factor (SRF) and its coactivator and oncogene, megakaryoblastic leukemia 1 (MKL1). Inhibitors of this pathway could serve as useful biological probes and potential cancer therapeutic agents. Through a transcription-based high-throughput serum response element-luciferase screening assay, we identified two small-molecule inhibitors of this pathway. Mechanistic studies on the more potent CCG-1423 show that it acts downstream of Rho because it blocks SRE.L-driven transcription stimulated by Galpha(12)Q231L, Galpha(13)Q226L, RhoA-G14V, and RhoC-G14V. The ability of CCG-1423 to block transcription activated by MKL1, but not that induced by SRF-VP16 or GAL4-VP16, suggests a mechanism targeting MKL/SRF-dependent transcriptional activation that does not involve alterations in DNA binding. Consistent with its role as a Rho/SRF pathway inhibitor, CCG-1423 displays activity in several in vitro cancer cell functional assays. CCG-1423 potently (<1 mumol/L) inhibits lysophosphatidic acid-induced DNA synthesis in PC-3 prostate cancer cells, and whereas it inhibits the growth of RhoC-overexpressing melanoma lines (A375M2 and SK-Mel-147) at nanomolar concentrations, it is less active on related lines (A375 and SK-Mel-28) that express lower levels of Rho. Similarly, CCG-1423 selectively stimulates apoptosis of the metastasis-prone, RhoC-overexpressing melanoma cell line (A375M2) compared with the parental cell line (A375). CCG-1423 inhibited Rho-dependent invasion by PC-3 prostate cancer cells, whereas it did not affect the Galpha(i)-dependent invasion by the SKOV-3 ovarian cancer cell line. Thus, based on its profile, CCG-1423 is a promising lead compound for the development of novel pharmacologic tools to disrupt transcriptional responses of the Rho pathway in cancer.

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    • "This is one of the major pathways activated within epithelial cells by the combination of TGFβ and matrix rigidity [99]. In addition, small molecule inhibitors including CCG-1423 and its analogs block SRF/MRTFA signaling [191,192]. Namely, CCG-1423 blocks the interaction of MRTFA with importin alpha/beta 1 thus preventing the nuclear import of MRTFA [193]. Furthermore, CCG-1423 has been shown to successfully inhibit TGFβ-induced expression of αSMA [102,104,194]. "
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    • "3). A drug inhibiting MKL1-dependent transcription, CCG-1423 (Evelyn et al., 2007), is already available, but more investigations should be performed to reveal a potential relevance to breast cancer treatment. "
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    • "CCG-1423 was originally identified as an inhibitor of RhoA signaling [21]. Although CCG-1423 has been reported to block the nuclear accumulation of MRTF-A [22], [23], the molecular mechanism is yet to be determined. "
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Chris R Evelyn