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: 5.68). 08/2007; 6(8):2249-60. DOI: 10.1158/1535-7163.MCT-06-0782
Source: PubMed


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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    Clinical and Translational Medicine 07/2014; 3(1):23. DOI:10.1186/2001-1326-3-23
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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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    ABSTRACT: Estrogen receptor alpha (ERα) is generally considered to be a good prognostic marker because almost 70% of ERα-positive tumors respond to anti-hormone therapies. Unfortunately, during cancer progression, mammary tumors can escape from estrogen control, resulting in resistance to treatment. In this study, we demonstrate that activation of the actin/megakaryoblastic leukemia 1 (MKL1) signaling pathway promotes the hormonal escape of estrogen-sensitive breast cancer cell lines. The actin/MKL1 signaling pathway is silenced in differentiated ERα-positive breast cancer MCF-7 and T47D cell lines and active in ERα-negative HMT-3522 T4-2 and MDA-MB-231 breast cancer cells, which have undergone epithelial-mesenchymal transition. We showed that MKL1 activation in MCF-7 cells, either by modulating actin dynamics or using MKL1 mutants, down-regulates ERα expression and abolishes E2-dependent cell growth. Interestingly, the constitutively active form of MKL1 represses PR and HER2 expression in these cells and increases the expression of HB-EGF, TGFβ, and amphiregulin growth factors in an E2-independent manner. The resulting expression profile (ER-, PR-, HER2-) typically corresponds to the triple-negative breast cancer expression profile.
    Molecular and Cellular Endocrinology 06/2014; 390(1). DOI:10.1016/j.mce.2014.03.009 · 4.41 Impact Factor
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    • "We recently identified in high-throughput screens, a compound, CCG-1423, that blocks MRTF nuclear localization by interfering with the regulation of intranuclear actin polymerization mediated by microtubule-associated mono-oxygenase, calponin and LIM domain–containing 2 (MICAL-2) (Evelyn et al., 2007; Lundquist et al., 2014). CCG-1423 is more effective than ROCK inhibitors in reducing SRF-mediated transcription (Evelyn et al., 2007). Several groups have used this compound to interdict myofibroblast formation (Sandbo et al., 2009; Zhou et al., 2013), and it was recently shown to have in vivo activity in a chlorhexidine gluconate model of peritoneal fibrosis (Sakai et al., 2013). "
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    ABSTRACT: Systemic sclerosis (SSc) or scleroderma, like many fibrotic disorders, lacks effective therapies. Current trials focus on anti-inflammatory drugs or targeted approaches aimed at one of the many receptor mechanisms initiating fibrosis. In light of evidence that a myocardin-related transcription factor (MRTF) and serum response factor (SRF)-regulated gene transcriptional program induced by Rho GTPases is essential for myofibroblast activation, we explore the hypothesis that inhibitors of this pathway may represent novel antifibrotics. MRTF-SRF-regulated genes show spontaneously increased expression in primary dermal fibroblasts from patients with diffuse cutaneous SSc. A novel small-molecule inhibitor of MRTF/SRF-regulated transcription (CCG-203971) inhibits expression of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA), and collagen 1 (COL1A2) in both SSc fibroblasts and in LPA- and transforming growth factor β (TGFβ)-stimulated fibroblasts. In vivo treatment with CCG-203971 also prevented bleomycin-induced skin thickening and collagen deposition. Thus targeting the MRTF/SRF gene transcription pathway could provide an efficacious new approach to therapy for SSc and other fibrotic disorders.
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Chris R Evelyn