更新于：2024-11-21

CCG-1423

更新于：2024-11-21

概要

研发状态

概要

基本信息

药物类型

小分子化药

别名

靶点

MRTFA x RHOA

作用机制

MRTFA inhibitors(MKL myocardin like protein inhibitors)、RHOA抑制剂(ras homolog family member A inhibitors)

治疗领域-

在研适应症-

非在研适应症-

原研机构

Kyoto University

在研机构

Kyoto University

非在研机构-

最高研发阶段药物发现

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C18H13ClF6N2O3

InChIKeyDSMXVSGJIDFLKP-UHFFFAOYSA-N

CAS号285986-88-1

关联

100 项与 CCG-1423 相关的临床结果

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100 项与 CCG-1423 相关的转化医学

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100 项与 CCG-1423 相关的专利（医药）

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项与 CCG-1423 相关的文献（医药）

2024-11-01·Life Sciences

Macrophage MKL1 contributes to cardiac fibrosis in a mouse model of myocardial infarction

Article

作者: Kuai, Yameng ; Cao, Ke ; Yu, Wenkui ; Zhu, Yuwen ; Chen, Baoyu ; Zhao, Qianwen

AIMSCardiac fibrosis is characterized by aberrant collagen deposition in the heart. Macrophage polarization or infiltration is the main reason to accelerate the collagen deposition. We attempted to investigate the involvement of MKL1 in macrophages during the development of cardiac fibrosis.MATERIALS AND METHODSCardiac fibrosis is induced by myocardial infarction (MI). The MKL1^f/f mice were crossed to the Lyz2-cre mice to generate macrophage conditional MKL1 knockout mice (MKL1^ΔMφ). In addition, macrophage conditional MKL1 overexpression mice (MKL1^Mϕ-OE) were constructed by crossing Lyz2-cre mice to MKL1^{ΔN200-Rosa26} mice.KEY FINDINGSMKL1 expression was significantly increased in macrophages of both ischemic cardiomyopathy (ICM) patients and mice induced to develop myocardial infarction. Deletion of MKL1 in macrophages improved the heart function after MI-induced cardiac fibrosis. Consistently, MKL1^Mϕ-OE mice displayed more severe cardiac fibrosis and worsened heart function than the control mice after MI. Moreover, administration of a small-molecule MKL1 inhibitor CCG-1423 also decreased the collagen deposition after MI.SIGNIFICANCEOur data demonstrate that MKL1 in macrophages contributes to cardiac fibrosis pathogenesis and reinforce the notion that targeting MKL1 may yield effective antifibrotic therapeutics in the heart.

2024-10-16·The Journal of Infectious Diseases

Inhibition of RhoA Prevents Cryptococcus neoformans Capsule Glucuronoxylomannan-Stimulated Brain Endothelial Barrier Disruption

Article

作者: Munzen, Melissa E ; Saytoo, Durvinand ; Dores, Michael R ; Reguera-Gomez, Marta ; Enriquez, Vanessa ; Mathew, Cristian ; Minhas, Amanjeet ; Martinez, Luis R ; Charles-Niño, Claudia L

AbstractCryptococcus neoformans (Cn) is an opportunistic fungus that causes severe central nervous system (CNS) disease in immunocompromised individuals. Brain parenchyma invasion requires fungal traversal of the blood-brain barrier. In this study, we describe that Cn alters the brain endothelium by activating small GTPase RhoA, causing reorganization of the actin cytoskeleton and tight junction modulation to regulate endothelial barrier permeability. We confirm that the main fungal capsule polysaccharide glucuronoxylomannan is responsible for these alterations. We reveal a therapeutic benefit of RhoA inhibition by CCG-1423 in vivo. RhoA inhibition prolonged survival and reduced fungal burden in a murine model of disseminated cryptococcosis, supporting the therapeutic potential of targeting RhoA in the context of cryptococcal infection. We examine the complex virulence of Cn in establishing CNS disease, describing cellular components of the brain endothelium that may serve as molecular targets for future antifungal therapies to alleviate the burden of life-threatening cryptococcal CNS infection.

2024-08-01·American Journal of Physiology-Cell Physiology

Regulation of the RhoA exchange factor GEF-H1 by profibrotic stimuli through a positive feedback loop involving RhoA, MRTF, and Sp1

Article

作者: Szászi, Katalin ; Connelly, Kim A. ; Rzepka, Mark F. ; Friedberg, Mark K. ; Venugopal, Shruthi ; Layne, Matthew D. ; Kofler, Michael ; Sri Theivakadadcham, Veroni S. ; Dan, Qinghong ; Kapus, András ; Wu, Brian

We show that expression of the RhoA regulator GEF-H1 is upregulated in tubular cells exposed to fibrogenic cytokines and in animal models of kidney and heart fibrosis. We identify a pathway wherein GEF-H1/RhoA-dependent MRTF activation through its noncanonical partner Sp1 upregulates GEF-H1. Our data reveal the existence of a positive feedback cycle that enhances Rho signaling through control of both GEF-H1 activation and expression. This feedback loop may play an important role in organ fibrosis.

项与 CCG-1423 相关的新闻（医药）

2023-01-30

·生物谷

Redox Biology: 靶向MK-2/MKL1/FOXM1轴可能是治疗再狭窄的合理途径

血管平滑肌细胞(VSMCs)表现出显著的灵活性，使它们能够适应(或失调)一系列不同的病理生理条件。血管平滑肌细胞(VSMCs)表现出显著的灵活性，使它们能够适应(或失调)一系列不同的病理生理条件。正常情况下，完全分化的VSMCs通过退出细胞周期并产生肌肉相关分子来执行血管的节律性收缩/扩张，从而对血管活性物质做出反应，从而采用收缩表型。然而，在通常被称为表型调制(PM)的过程中，VSMC可以在几种不同的形态和功能状态之间切换。PM被认为是血管损伤的关键因素，导致许多人类疾病的发病，包括动脉粥样硬化、主动脉瘤和肺动脉高压。图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1016/j.redox.2022.102586 近日，来自南京医科大学的研究者们在Redox Biology杂志上发表了题为“MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcription”的文章，该研究数据表明，氧化还原敏感的MKL1磷酸化开关激活FOXM1转录，并介导ROS刺激血管平滑肌增殖。靶向MK-2/MKL1/FOXM1轴可能是治疗再狭窄的合理途径。活性氧簇(ROS)通过刺激血管平滑肌细胞(VSMC)增殖，促进血管损伤和新生内膜的形成。然而，潜在的转录机制并不完全清楚。在本研究中，研究者报道了在经典的血管损伤模型中，血管平滑肌细胞特异性的MKL1缺失抑制了新生内膜的形成。同样，CCG-1423抑制MKL1活性的药物类似地缓和了小鼠的新生内膜形成。在血管平滑肌细胞中过表达具有结构性活性的MKL1以一种ROS依赖的方式促进增殖。相反，MKL1缺失或抑制可抑制VSMC的增殖。基于PCR阵列的筛选确定叉头盒蛋白M1(FOXM1)是MKL1的直接靶点。MKL1与E2F1相互作用，激活FOXM1表达。相应地，FOXM1缺失可改善MKL1依赖的VSMC的增殖。ROS通过MK2诱导MKL1磷酸化是其与E2F1相互作用并随后激活FOXM1的关键。更重要的是，在再狭窄患者的动脉标本中，FOXM1的表达与VSMC的增殖呈正相关。机制总结图图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1016/j.redox.2022.102586 综上所述，本研究的数据揭示了一个以前未知的MK2-MKL1-FOXM1轴，它作为一个氧化还原敏感的开关来调节VSMC的增殖和新生内膜的形成。鉴于MK2抑制剂和FOXM1抑制剂在模型动物中均显示出高效阻断新生内膜形成的结果，本研究结果为靶向MK2-MKL1-FOXM1轴是预防再狭窄的可行的治疗方法提供了新的理论基础。（生物谷 Bioon.com）参考文献 Teng Wu et al. MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcription. Redox Biol. 2023 Feb; 59:102586. doi: 10.1016/j.redox.2022.102586.