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Research Articles

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

Departments of ¹ Pharmacology and ² Internal Medicine and ³ University of Michigan Comprehensive Cancer Center, University of Michigan Medical Center, Ann Arbor, Michigan

Requests for reprints: Richard R. Neubig, Department of Pharmacology, University of Michigan Medical Center, 1301 MSRB III, Room 2220D, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0632. Phone: 734-763-3650; Fax: 734-763-4450. E-mail: RNeubig{at}umich.edu

Abstract

Lysophosphatidic acid receptors stimulate a G_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 G₁₂Q231L, G₁₃Q226L, 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 µmol/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 G_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. [Mol Cancer Ther 2007;6(8):2249–60]

Grant support: NIH grants R01GM39561 (R.R. Neubig), R01CA77612 (S.D. Merajver), and RO1DK61615 (J.A. Iñiguez-Lluhí); Burroughs Wellcome Fund (S.D. Merajver); Department of Defense (S.D. Merajver); Breast Cancer Research Foundation (S.D. Merajver); and University of Michigan Office of Research and Graduate Studies Translational Grant (R.R. Neubig and S.D. Merajver).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 12/18/06; revised 5/15/07; accepted 6/29/07.