1. Academic Validation
  2. CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling

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

  • Mol Cancer Ther. 2007 Aug;6(8):2249-60. doi: 10.1158/1535-7163.MCT-06-0782.
Chris R Evelyn 1 Susan M Wade Qin Wang Mei Wu Jorge A Iñiguez-Lluhí Sofia D Merajver Richard R Neubig
Affiliations

Affiliation

  • 1 Department of Pharmacology, University of Michigan Medical Center, 1301 MSRB III, Room 2220D, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0632, USA.
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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