Last update 01 Nov 2024

RHOA x MRTFA

Last update 01 Nov 2024

Basic Info

Related Targets

RHOAMRTFA

Drugs associated with RHOA x MRTFA

CCG-1423

Target

MRTFA x RHOA

Mechanism

MRTFA inhibitors [+1]

Active Org.

Kyoto University

Originator Org.

Kyoto University

Active Indication-

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with RHOA x MRTFA

100 Translational Medicine associated with RHOA x MRTFA

0 Patents (Medical) associated with RHOA x MRTFA

Literatures (Medical) associated with RHOA x MRTFA

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 Jun 2024·Cell Reports Medicine

Alarmin S100A8 imparts chemoresistance of esophageal cancer by reprogramming cancer-associated fibroblasts

Article

Author: Liu, Rucheng ; Chen, Xinjie ; Yang, Xinyu ; Lin, Dongxin ; Wu, Chen ; Ou, Zhengjie ; Zhu, Liang ; Zhang, Shaosen ; Cheng, Guoyu ; Tan, Wen ; Liu, Tianyuan

Chemotherapy remains the first-line treatment for advanced esophageal cancer. However, durable benefits are achieved by only a limited subset of individuals due to the elusive chemoresistance. Here, we utilize patient-derived xenografts (PDXs) from esophageal squamous-cell carcinoma to investigate chemoresistance mechanisms in preclinical settings. We observe that activated cancer-associated fibroblasts (CAFs) are enriched in the tumor microenvironment of PDXs resistant to chemotherapy. Mechanistically, we reveal that cancer-cell-derived S100A8 triggers the intracellular RhoA-ROCK-MLC2-MRTF-A pathway by binding to the CD147 receptor of CAFs, inducing CAF polarization and leading to chemoresistance. Therapeutically, we demonstrate that blocking the S100A8-CD147 pathway can improve chemotherapy efficiency. Prognostically, we found the S100A8 levels in peripheral blood can serve as an indicator of chemotherapy responsiveness. Collectively, our study offers a comprehensive understanding of the molecular mechanisms underlying chemoresistance in esophageal cancer and highlights the potential value of S100A8 in the clinical management of esophageal cancer.

01 Jan 2024·Acta Pharmacologica Sinica

Myeloid-derived growth factor suppresses VSMC dedifferentiation and attenuates postinjury neointimal formation in rats by activating S1PR2 and its downstream signaling

Article

Author: Liu, Xue ; Liu, Qian ; Li, Hou-Wei ; Zhao, Yi-Xiu ; Ren, Jing ; Chen, Yi ; Zhan, Ting-Ting ; Feng, Min ; Zhang, Yan ; Wang, Zhi-Qi ; Wang, Zheng-Kai ; Jiang, Wen-Yu ; Li, Xue ; Ma, Chun-Yue ; Zhao, Yu ; Cao, Shi-Feng ; Jin, Lu-Ying ; Tian, Jia-Ying ; Yang, Shuang

Restenosis after angioplasty is caused usually by neointima formation characterized by aberrant vascular smooth muscle cell (VSMC) dedifferentiation. Myeloid-derived growth factor (MYDGF), secreted from bone marrow-derived monocytes and macrophages, has been found to have cardioprotective effects. In this study we investigated the effect of MYDGF to postinjury neointimal formation and the underlying mechanisms. Rat carotid arteries balloon-injured model was established. We found that plasma MYDGF content and the level of MYDGF in injured arteries were significantly decreased after balloon injury. Local application of exogenous MYDGF (50 μg/mL) around the injured vessel during balloon injury markedly ameliorated the development of neointimal formation evidenced by relieving the narrow endovascular diameter, improving hemodynamics, and reducing collagen deposition. In addition, local application of MYDGF inhibited VSMC dedifferentiation, which was proved by reversing the elevated levels of osteopontin (OPN) protein and decreased levels of α-smooth muscle actin (α-SMA) in the left carotid arteries. We showed that PDGF-BB (30 ng/mL) stimulated VSMC proliferation, migration and dedifferentiation in vitro; pretreatment with MYDGF (50-200 ng/mL) concentration-dependently eliminated PDGF-BB-induced cell proliferation, migration and dedifferentiation. Molecular docking revealed that MYDGF had the potential to bind with sphingosine-1-phosphate receptor 2 (S1PR2), which was confirmed by SPR assay and Co-IP analysis. Pretreatment with CCG-1423 (Rho signaling inhibitor), JTE-013 (S1PR2 antagonist) or Ripasudil (ROCK inhibitor) circumvented the inhibitory effects of MYDGF on VSMC phenotypic switching through inhibiting S1PR2 or its downstream RhoA-actin monomers (G-actin) /actin filaments (F-actin)-MRTF-A signaling. In summary, this study proves that MYDGF relieves neointimal formation of carotid arteries in response to balloon injury in rats, and suppresses VSMC dedifferentiation induced by PDGF-BB via S1PR2-RhoA-G/F-actin-MRTF-A signaling pathway. In addition, our results provide evidence for cross talk between bone marrow and vasculature.

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