Last update 01 Nov 2024

SRF x MRTFA

Last update 01 Nov 2024

Basic Info

Related Targets

SRFMRTFA

Drugs associated with SRF x MRTFA

CCG-203971

Target

MRTFA x SRF

Mechanism

MRTFA inhibitors [+1]

Active Org.

Genesis Biosciences LLC [+3]

Originator Org.

Genesis Biosciences LLC

Active Indication

Glaucoma, Open-Angle [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with SRF x MRTFA

100 Translational Medicine associated with SRF x MRTFA

0 Patents (Medical) associated with SRF x MRTFA

291

Literatures (Medical) associated with SRF x MRTFA

01 Oct 2024·Molecular Biology of the Cell

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

Article

Author: 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.

01 Sep 2024·Molecular Therapy: Oncology

Identification of novel inhibitors of the transcriptional coactivator MRTF-A for HCC therapy

Article

Author: Chubanov, Vladimir ; Muehlich, Susanne ; Kyheröinen, Salla ; Vartiainen, Maria Kristina ; Rupprecht, Laura ; Gudermann, Thomas ; Franz, Miriam Jasmin ; Heinrich, Markus R. ; Wenisch, Pia ; Heinrich, Markus R ; Wohlleben, Petra

Myocardin-related transcription factor A (MRTF-A) is a coactivator of serum response factor (SRF), which regulates the expression of genes involved in cell proliferation, migration, and differentiation and has been implicated in hepatocellular carcinoma (HCC) progression. We recently established inhibition of the transcriptional activity of MRTF-A by NS8593 as a novel therapeutic approach for HCC therapy. NS8593 is a negative gating modulator of the transient receptor potential cation channel TRPM7. In this report, we identify an aminobenzimidazole that is highly potent in inhibiting TRPM7 and its interaction with RhoA, leading to decreased SRF transcriptional activity and enhanced nuclear export of MRTF-A, as determined by fluorescence loss in photobleaching (FLIP). This resulted in reduced expression of the MRTF/SRF target genes transforming growth factor β1 (TGF-β1) and tetraspanin 5 (TSPAN5), senescence induction, and growth arrest in HCC cells. Replacement of the tetraline core by a 3-aminophenyl substructure yielded inhibitor 10 with higher potency than inhibitor 5, and further structural modifications yielded highly potent inhibitors of SRF activity, 14 and 16. Both compounds were capable of inhibiting cell proliferation and inducing senescence in HCC cells with improved efficacy compared to NS8593. These inhibitors represent valuable tools for understanding the molecular basis of drug development targeting TRPM7 and MRTFs.

01 Sep 2024·American Journal of Obstetrics and Gynecology

Altered extracellular matrix–related pathways accelerate the transition from normal to prefibroid myometrium in Black women

Article

Author: Al-Hendy, Ayman ; Bariani, Maria Victoria ; Ali, Mohamed ; Grimm, Sandra L ; Coarfa, Cristian ; Velez Edwards, Digna R ; Yang, Qiwei ; Walker, Cheryl L

BACKGROUNDBlack women experience a disproportionate impact of uterine fibroids compared to White women, including earlier diagnosis, higher frequency, and more severe symptoms. The etiology underlying this racial disparity remains elusive.OBJECTIVEThe aim of this study was to evaluate the molecular differences in normal myometrium (fibroid-free uteri) and at-risk myometrium (fibroid-containing uteri) tissues in Black and White women.STUDY DESIGNWe conducted whole-genome RNA-seq on normal and at-risk myometrium tissues obtained from both self-identified Black and White women (not Hispanic or Latino) to determine global gene expression profiles and to conduct enriched pathway analyses (n=3 per group). We initially assessed the differences within the same type of tissue (normal or at-risk myometrium) between races. Subsequently, we analyzed the transcriptome of normal myometrium compared to at-risk myometrium in each race and determined the differences between them. We validated our findings through real-time PCR (sample size range=5-12), western blot (sample size range=5-6), and immunohistochemistry techniques (sample size range=9-16).RESULTSThe transcriptomic analysis revealed distinct profiles between Black and White women in normal and at-risk myometrium tissues. Interestingly, genes and pathways related to extracellular matrix and mechanosensing were more enriched in normal myometrium from Black than White women. Transcription factor enrichment analysis detected greater activity of the serum response transcription factor positional motif in normal myometrium from Black compared to White women. Furthermore, we observed increased expression levels of myocardin-related transcription factor-serum response factor and the serum response factor in the same comparison. In addition, we noted increased expression of both mRNA and protein levels of vinculin, a target gene of the serum response factor, in normal myometrium tissues from Black women as compared to White women. Importantly, the transcriptomic profile of normal to at-risk myometrium conversion differs between Black and White women. Specifically, we observed that extracellular matrix-related pathways are involved in the transition from normal to at-risk myometrium and that these processes are exacerbated in Black women. We found increased levels of Tenascin C, type I collagen alpha 1 chain, fibronectin, and phospho-p38 MAPK (Thr180/Tyr182, active) protein levels in at-risk over normal myometrium tissues from Black women, whereas such differences were not observed in samples from White women.CONCLUSIONThese findings indicate that the racial disparities in uterine fibroids may be attributed to heightened production of extracellular matrix in the myometrium in Black women, even before the tumors appear. Future research is needed to understand early life determinants of the observed racial differences.

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