预约演示

更新于：2025-05-07

SRF x MRTFA

更新于：2025-05-07

基本信息

关联

项与 SRF x MRTFA 相关的药物

CCG-203971

靶点

MRTFA x SRF

作用机制

MRTFA inhibitors [+1]

在研机构

Genesis Biosciences LLC

原研机构

Genesis Biosciences LLC

在研适应症

2型糖尿病

非在研适应症

开角型青光眼

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 SRF x MRTFA 相关的临床结果

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100 项与 SRF x MRTFA 相关的转化医学

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0 项与 SRF x MRTFA 相关的专利（医药）

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287

项与 SRF x MRTFA 相关的文献（医药）

2025-05-01·Matrix Biology

Inhibition of the MRTF-A/SRF signaling axis alleviates vocal fold scarring

Article

作者: Lefebvre, Véronique ; Truong, Huy D ; Friedman, Ryan M ; Zur, Karen B ; Chen, Jeffrey F ; Gottardi, Riccardo ; Brown, Elizabeth A ; Angelozzi, Marco ; Aronson, Matthew R

Vocal fold scarring, the most common cause of poor voice after airway injury, involves the transition of vocal fold fibroblasts to contractile myofibroblasts. Vocal fold myofibroblasts can be characterized by significant extracellular matrix (ECM) secretion and stress fiber formation. Biochemical signals, such as transforming growth factor (TGF)-β1, and biophysical cues, such as matrix stiffening, have been shown to induce the fibroblast-to-myofibroblast transition. To identify key intracellular pathways that may mediate myofibroblast activation, we performed bulk RNA sequencing of human vocal fold fibroblasts treated with or without TGF-β1 and found that genes downstream of myocardin related transcription factor A (MRTF-A) and serum response factor (SRF) were upregulated in TGFβ1-induced myofibroblasts. We then show that both TGF-β1 and ECM stiffening induce MRTF-A and SRF nuclear translocation during vocal fold myofibroblast activation. Inhibition of MRTF-A via CCG-257,081 reduced pro-fibrotic gene expression, the percentage of α-smooth muscle actin (α-SMA)-positive fibroblasts, and cell contractility in vitro. In a murine model of vocal fold scarring, MRTF-A inhibition reduced vocal fold scarring severity, evidenced by reduced epithelial thickening, decreased glycosaminoglycan content, and collagen deposition, and decreased expression of ACTA2. Our study suggests that the MRTF-A/SRF pathway regulates vocal fold myofibroblast activation, and that inhibition of MRTF-A has a protective effect against vocal fold scarring in mice.

2025-03-14·Cancer Research

MICAL2 Promotes Pancreatic Cancer Growth and Metastasis

Article

作者: Commisso, Cosimo ; Gallinger, Steven ; Sheik Pran Babu, Deepa ; Tamayo, Pablo ; Jang, Gun Ho ; Courelli, Asimina S. ; Sood, Divya ; Garg, Bharti ; Martsinkovskiy, Alexei ; Aggarwal, Neetu ; Goodfellow, Elliot ; D’Ippolito, Anthony ; Lambies, Guillem ; Johnston, Brian ; Tiriac, Hervé ; Lowy, Andrew M. ; Brodt, Pnina ; Wenzel, Alexander T. ; Jaque, Katelin ; Gulay, Kevin Christian Montecillo ; Sharma, Shweta ; Mesirov, Jill P. ; Patel, Jay ; Esparza, Edgar ; Khan, Sohini ; Austgen, Kathryn ; Rajbhandari, Nirakar ; Orlando, David A. ; Panneerpandian, Ponmathi ; Mose, Evangeline S. ; Jaquish, Dawn

AbstractPancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers; thus, identifying more effective therapies is a major unmet need. In this study, we characterized the super-enhancer (SE) landscape of human PDAC to identify drivers of the disease that might be targetable. This analysis revealed MICAL2 as an SE-associated gene in human PDAC, which encodes the flavin monooxygenase enzyme that induces actin depolymerization and indirectly promotes serum response factor transcription by modulating the availability of serum response factor coactivators such as myocardin-related transcription factors (MRTF-A and MRTF-B). MICAL2 was overexpressed in PDAC, and high-MICAL2 expression correlated with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and epithelial–mesenchymal transition signaling pathways, contributing to tumor growth and metastasis. In loss- and gain-of-function experiments in human and mouse PDAC cells, MICAL2 promoted both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 also inhibited macropinocytosis. MICAL2, MRTF-A, and MRTF-B influenced PDAC cell proliferation and migration and promoted cell-cycle progression in vitro. Importantly, MICAL2 supported in vivo tumor growth and metastasis. Interestingly, MRTF-B, but not MRTF-A, phenocopied MICAL2-driven phenotypes in vivo. This study highlights the multiple ways in which MICAL2 affects PDAC biology and provides a foundation for future investigations into the potential of targeting MICAL2 for therapeutic intervention.Significance: Characterization of the epigenomic landscape of pancreatic cancer to identify early drivers of tumorigenesis uncovered MICAL2 as a super-enhancer–associated gene critical for tumor progression that represents a potential pharmacologic target.

2024-10-01·Molecular Biology of the Cell

mDia2 is an important mediator of MRTF-A-dependent regulation of breast cancer cell migration

Article

作者: Joy, Marion ; Chawla, Pooja ; Lucas, Peter C. ; Roy, Partha ; Chen, Fangyuan ; Yu, Virginia ; Gau, David ; Antonello, Jacob ; Lee, Adrian V. ; Boone, David ; Eder, Ian

Dysregulated actin cytoskeleton gives rise to aberrant cell motility and metastatic spread of tumor cells. This study evaluates the effect of overexpression of wild-type versus functional mutants of MRTF-A on migration and invasion of breast cancer (BC) cells. Our studies indicate that SRF's interaction is critical for MRTF-A-induced promotion of both two-dimensional and three-dimensional cell migration, while the SAP-domain function is important selectively for three-dimensional cell migration. Increased MRTF-A activity is associated with more effective membrane protrusion, a phenotype that is attributed predominantly to SRF's interaction with MRTF. We demonstrate formin-family protein mDia2 as an important mediator of MRTF-stimulated actin polymerization at the leading edge and cell migration. Multiplexed quantitative immunohistochemistry and transcriptome analyses of clinical BC specimens further demonstrate a positive correlation between nuclear localization of MRTF with malignant traits of cancer cells and enrichment of MRTF–SRF gene signature in pair-matched distant metastases versus primary tumors. In conclusion, this study establishes a novel mechanism of MRTF-dependent regulation of cell migration and provides evidence for the association between MRTF activity and increased malignancy in human BC, justifying future development of specific small molecule inhibitors of the MRTF-SRF transcriptional complex as potential therapeutic agents in BC.

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