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

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.

• Authors: Chris R Evelyn, Susan M Wade, Qin Wang, Mei Wu, Jorge A Iñiguez-Lluhí, Sofia D Merajver, Richard R Neubig
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 8 Pg. 2249-60 (Aug 2007) ISSN: 1535-7163 [Print] United States
• PMID: 17699722 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anilides
• Antineoplastic Agents
• Benzamides
• CCG 1423
• Luciferases
• rhoA GTP-Binding Protein

Topics

• Anilides (pharmacology)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Benzamides (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Humans
• Luciferases (metabolism)
• Mice
• NIH 3T3 Cells
• Neoplasm Invasiveness
• Neoplasms (pathology)
• Serum Response Element (genetics)
• Signal Transduction (drug effects)
• Transcription, Genetic (drug effects)
• rhoA GTP-Binding Protein (antagonists & inhibitors, genetics)