Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma

Hutchings, Kim; Lisabeth, Erika M.; Rajeswaran, W. G.; Wilson, Michael W.; Sorenson, Roderick J.; Campbell, Phillip L.; Ruth, Jeffrey H.; Amin, Asif; Tsou, Pei Suen; Leipprandt, Jeffrey R.; Olson, Samuel R.; Wen, Bo; Zhao, Ting C.; Sun, Duxin; Khanna, Dinesh; Fox, David A.; Neubig, Richard R.; Larsen, Scott D.

doi:10.1016/j.bmcl.2017.02.070

Cited by 45 publications

(55 citation statements)

References 18 publications

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“…To investigate the role of the MRTF/SRF pathway in the regulation of FGFR1 in hMSCs, we inhibited the pathway using CCG203971 [48,49] . Indeed, in both hMSCs and fibroblasts, inhibition of the MRTF/SRF pathway reduced FGFR1 expression by 59.6±7.0% (p<0,01) and 61.5±2.9% (p<0.01), respectively (Fig 5a, c).…”

Section: Actin-myosin and Mrtf/srf Pathway Regulate Fgfr1 Expressionmentioning

confidence: 99%

Mechanosensitive regulation of FGFR1 through the MRTF-SRF pathway

Zonderland

Rezzola

Moroni

2019

Preprint

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Controlling basic fibroblast growth factor (bFGF) signaling is important for both tissueengineering purposes, controlling proliferation and differentiation potential, and for cancer biology, influencing tumor progression and metastasis. Here, we observed that human mesenchymal stromal cells (hMSCs) no longer responded to soluble or covalently bound bFGF when cultured on microfibrillar substrates, while fibroblasts did. This correlated with a downregulation of FGF receptor 1 (FGFR1) expression of hMSCs on microfibrillar substrates, compared to hMSCs on conventional tissue culture plastic (TCP). hMSCs also expressed less SRF on ESP scaffolds, compared to TCP, while fibroblasts maintained high FGFR1 and SRF expression. Inhibition of actin-myosin tension or the MRTF/SRF pathway decreased FGFR1 expression in hMSCs, fibroblasts and MG63 osteosarcoma cells. This downregulation was functional, as hMSCs became irresponsive to bFGF in the presence of MRTF/SRF inhibitor. Together, our data show that hMSCs, but not fibroblasts, are irresponsive to bFGF when cultured on microfibrillar susbtrates by downregulation of FGFR1 through the MRTF/SRF pathway. This is the first time FGFR1 expression has been shown to be mechanosensitive and adds to the sparse literature on FGFR1 regulation. These results could open up new targets for cancer treatments and could aid designing tissue engineering constructs that better control cell proliferation.

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Section: Actin-myosin and Mrtf/srf Pathway Regulate Fgfr1 Expressionmentioning

confidence: 99%

Mechanosensitive regulation of FGFR1 through the MRTF-SRF pathway

Zonderland

Rezzola

Moroni

2019

Preprint

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“…CCG-222740, previously reported by Hutchings et al (30), was a kind gift of Scott Larsen at the Vahltechich Medicinal Chemistry Core (Ann Arbor, MI). CCG-222740 was dissolved in DMSO in 10 mM aliquots and stored at -20 °C.…”

Section: Inhibitorsmentioning

confidence: 99%

“…Through structure-activity relationship optimization of CCG-203971, we recently reported the analog CCG-222740 with increased potency of MRTF-pathway inhibition in primary human dermal fibroblasts (30). Additionally, CCG-222740 demonstrated a greater inhibitory effect on MRTF/SRF target genes (ACTA2 and CTGF) and lesser cytotoxicity than CCG-203971 in a preclinical model of fibrosis (31).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Myocardin-Related Transcription Factor pathway increases efficacy of Trametinib in NRAS-mutant melanoma cell lines

Appleton

Palsuledesai

Misek

et al. 2019

Preprint

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The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (~50% BRAF V600 mutations and ~30% NRAS mutations). While targeted therapies have yielded success in BRAF V600 mutant melanoma patients, such therapies have been ineffective in NRAS mutant melanomas in part due to their cytostatic effects and primary resistance in this patient population. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. Combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells which have a high level of trametinib resistance. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlights the potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

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“…Vemurafenib (#S1267), Y-27632 (#S1049), fasudil (#S1573), and dasatinib (#S1021) were purchased from Sellekchem, Houston, TX, USA. CCG-222740 15 was synthesized in the lab of Dr. Scott Larsen at the University of Michigan. All compounds were diluted in DMSO to a stock concentration of 10 mM.…”

Section: Compounds and Antibodiesmentioning

confidence: 99%

“…Silencing of MRTF or SRF, a transcription factor by which MRTF modulates gene expression, prevents melanoma metastasis 24 . Previously, we have developed a series of MRTF-pathway inhibitors including CCG-203971 and CCG-222740 1, 10,15 and demonstrated that CCG-203971 prevents melanoma metastasis, induces G1 cell cycle arrest, and reduces growth of melanoma cells 10 . YAP1 has been shown to promote BRAFi/MEKi resistance in melanoma through suppression of apoptosis via BCL-xL and BIM dysgulation 7, 14, 17, 22 ; accumulation of YAP1 protein and enrichment of a YAP1 gene signature has been documented in about 40% of clinical melanoma samples from patients who relapsed on MAPK inhibitor therapies 14 .…”

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confidence: 99%

Rho-mediated gene transcription promotes BRAF inhibitor resistance in de-differentiated melanoma cells

Misek

Appleton

Dexheimer

et al. 2018

Preprint

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Over half of cutaneous melanoma tumors have BRAFV600E/K mutations. Acquired resistance to BRAF inhibitors (BRAFi) remains a major hurdle in attaining durable therapeutic responses. In this study we demonstrate that approximately 50-60% of melanoma cell lines with vemurafenib resistance acquired in vitro show activation of RhoA family GTPases. In BRAFi-resistant melanoma cell lines and tumors, activation of RhoA is correlated with decreased expression of melanocyte lineage genes. Using a machine learning approach, we built gene expression-based models to predict drug sensitivity for 265 common anti-cancer compounds. We then projected these signatures onto the collection of TCGA cutaneous melanoma and found that poorly differentiated tumors were predicted to have increased sensitivity to multiple Rho kinase (ROCK) inhibitors. Two transcriptional effectors downstream of Rho, MRTF and YAP1, are activated in the RhoHigh BRAFi-resistant cell lines, and resistant cells are more sensitive to inhibition of these transcriptional mechanisms. Taken together, these results support the concept of targeting Rho-regulated gene transcription pathways as a promising therapy approach to restore sensitivity to BRAFi-resistant tumors or as a combination therapy to prevent the onset of drug resistance.

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Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma

Cited by 45 publications

References 18 publications

Mechanosensitive regulation of FGFR1 through the MRTF-SRF pathway

Mechanosensitive regulation of FGFR1 through the MRTF-SRF pathway

Inhibition of the Myocardin-Related Transcription Factor pathway increases efficacy of Trametinib in NRAS-mutant melanoma cell lines

Rho-mediated gene transcription promotes BRAF inhibitor resistance in de-differentiated melanoma cells

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