2. GPCR/G Protein MAPK/ERK Pathway
  3. Ras
  4. AH001

AH001 是一种有口服活性的 RhoA 抑制剂，能够与 RhoA 内靠近 GDP 的一个隐秘口袋相结合的化合物，结合亲和力为 73.16 nM。AH001 通过与 GDP 作用，稳定 RhoA 与其内源性抑制剂 RhoGDIα 的相互作用。AH001 减少下游 MRTFA 的核易位，并下调纤维化/肥大相关蛋白。AH001 在多种心力衰竭动物模型以及 3D 心肌组织模型中减轻心肌重塑。AH001 通过 RhoA-RhoGDIα 轴发挥其心脏保护作用，有效抑制下游 RhoA 激活信号。

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AH001

AH001 Chemical Structure

CAS No. : 1456769-95-1

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  • 生物活性

  • 纯度 & 产品资料

  • 参考文献

生物活性

AH001 is a orally active RhoA inhibitor, which binds a cryptic pocket proximate to GDP within RhoA with a KD of 73.16 nM. AH001 interacts with GDP, stabilizing RhoA’s interaction with its endogenous inhibitor, RhoGDIα. AH001 reduces the downstream MRTFA nuclear translocation and downregulates fibrosis/hypertrophy proteins. AH001 mitigates myocardial remodeling in multiple HF animal models, and in the 3D myocardial tissue model. AH001 exerts its cardioprotective effects through the RhoA-RhoGDIα axis, effectively inhibiting downstream RhoA activation signaling[1].

体外研究
(In Vitro)

AH001 (20 μM) 降低 HEK 293F 细胞中 RhoA-GTP 的水平[1]。

AH001 (7.8-1000 nM) 降低 HEK 293F 细胞中 RhoA GTP/GDP 交换比率的作用具有浓度依赖性，IC50 值为 25.72 nM[1]。

AH001 (20 μM) 在 HEK 293F 细胞中与 RhoA-GDP 相互作用并稳定 RhoA-RhoGDIα 的结合，从而将 RhoA 限制在 GDP 结合状态[1]。

AH001 (10-40 μM, 24 h) 通过减少 RhoA-GTP 水平 (20 μM)、F-肌动蛋白形成以及 MRTFA 的核转位来抑制 RhoA 激活的下游信号传导[1]。

AH001 (10-40 μM, 24 h) 降低成纤维细胞中纤维化相关蛋白的水平，包括 FN1 和 COL3[1]。

AH001 (10-40 μM, 24 h) 有效抑制成纤维细胞的增殖，从而在 3D 心肌组织模型中以剂量依赖性方式减轻心肌细胞的病理性收缩[1]。

AH001 (20 μM, 24 h) 以 RhoGDIα 依赖性方式发挥其抗纤维化作用，并稳定 RhoA-RhoGDIα 复合物，以抑制成纤维细胞的增殖和激活，促进心肌细胞存活，并阻断 3D 心肌组织模型中促纤维化的 MRTFA 信号传导[1]。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

AH001 相关抗体:

Cell Migration Assay [1]

Cell Line: Cardiac fibroblasts
Concentration: 10, 20, and 40 μM
Incubation Time: 24 h
Result: Inhibited the migration of cardiac fibroblasts.

Western Blot Analysis[1]

Cell Line: Cardiac fibroblasts
Concentration: 10, 20, and 40 μM
Incubation Time: 24 h
Result: Decreased the level of RhoA-GTP in cardiac fibroblasts, cardiomyocytes.
Decreased levels of Fibronectin 1 (FN1), Collagen type III (COL3), Serum Response Factor (SRF), Vimentin (VIM), and the phosphorylation of Cofilin (CFN) in fibroblasts.

Immunofluorescence[1]

Cell Line: Cardiac fibroblasts, cardiomyocytes, 3D myocardial tissue model (cardiomyocytes and fibroblasts)
Concentration: 10, 20, and 40 μM
Incubation Time: 24 h
Result: Decreased the level of F-actin formation and nuclear translocation of MRTFA in cardiac fibroblasts and cardiomyocytes.
Acted on RhoA-RhoGDIα axis to inhibit the downstream signaling of RhoA activation in cardiomyocytes.
Reduced the expression levels of α-SMA and Vimentin in the 3D myocardial tissue model.
Decreased colocalization of RhoA and RhoGDIα in the 3D myocardial tissue model.
体内研究
(In Vivo)

AH001 减轻多种心力衰竭动物模型中的心肌重塑[1]。

AH001 (15.16-166.64 μM) 可减轻 2 日龄斑马鱼中异丙肾上腺素 (ISO) (HY-B1670A) 诱导的心肌肥厚中的心肌重塑[1]。

AH001 (10 mg/kg, i.g., 4 weeks) 可减轻血管紧张素II (Ang II) (HY-13948) 诱导的小鼠 (8 周龄) 模型中的心肌重塑[1]。

AH001 (3-30mg/kg, i.g., 1 weeks) 可减轻 8 周龄 LAD 小鼠和大鼠模型中的心肌重塑[1]。

AH001 (1-50 mg/kg, i.g., 12 days) 可减轻 8 周龄小鼠多柔比星 (Dox) (HY-15142A) 诱导的心脏毒性模型中的心肌重塑[1]。

AH001  (10 mg/kg, i.g., 1 weeks) 在 LAD 小鼠中通过 RhoA-RhoGDIα 轴发挥其心脏保护作用，有效抑制下游 RhoA 激活信号[1]。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: Isopropyl hyperglandrin (ISO)-induced cardiomyocyte hypertrophy models in zebrafish at 2 dpf[1].
Dosage: 15.16, 50.49, 166.64 μM
Administration: In the minimum for 3days
Result: Improved the ISO-induced myocardial hypertrophy, the ejection fraction (EF), the fractional shortening (FS), the blood flow rate, ventricular area, and cardiomyocyte area in zebrafishes with the minimum dose of 15.16 μM, which is comparable to LCZ696 at the dose of 69.59 μM.
Animal Model: Angiotensin II (HY-13948) (Ang II)-induced models in 8-week-old mice[1].
Dosage: 10 mg/kg
Administration: Oral gavage for 4 weeks after 3 mg/kg/day for 28 days of Ang II (osmotic minipumps)
Result: Improved cardiac functions comparable to the mice treated with LCZ696 at 66.67 mg/kg, assessed by echocardiography, Masson’s trichrome staining, and wheat germ agglutinin (WGA) staining.
Elevated EF and FS, reduced fibrosis areas, and decreased cardiomyocyte areas.
Restored the systolic blood pressure (SBP) and the diastolic blood pressure (DBP) to normal levels.
Animal Model: Left anterior descending (LAD) coronary artery ligation models in 8-week-old mice and rats[1].
Dosage: 3, 10, 30 mg/kg
Administration: Oral gavage for 1 week
Result: Improved cardiac functions at the minimum dose of 3 mg/kg, which is comparable to LCZ696 (66.67 mg/kg) in mice.
Reduced levels of NT-proBNP, lactate dehydrogenase (LDH), creatine kinase (CK), and Ang II in mice.
Reversed the upregulation expression of Rhoa, Postn, Acta2, and Runx1, Spp1 (Osteopontin, OPN) in mice (scRNA-seq) at 10 mg/kg.
Downregulated expression of Rhoa and Nppa (Precursor of ANP, a marker for HF) in mice (scRNA-seq) at 10 mg/kg.
Exhibited moderate Mrtfa expression levels in approximately 20% of cardiomyocytes in mice (scRNA-seq) at 10 mg/kg.
Reduced the levels of NT-proBNP, LDH, CK, and BNP in rats.
Animal Model: Doxorubicin (HY-15142A) (Dox)-induced cardiotoxicity models in 8-week-old mice[1].
Dosage: 1, 10, 50 mg/kg
Administration: Oral gavage for 12 days after 5 mg/kg/week for 4 weeks of DOX (i.p.)
Result: Significantly improved cardiac functions and the extent of myocardial injury.
Improved cardiac vacuole index and fibrosis in the heart (H&E staining and Sirius red staining).
Animal Model: LAD models in myocardium-specific RhoGDIα knockout mice[1].
Dosage: 10 mg/kg.
Administration: Oral gavage for 1 week
Result: Genetic ablation of RhoGDIα substantially attenuated the therapeutic effects of AH001, as evidenced by impaired recovery of cardiac function indicators, persistent fibrotic remodeling, unaltered myocardial hypertrophy, and no significant improvement in fibrosis areas or cardiomyocyte areas.
分子量

166.22

Formula

C10H14O2
CAS 号
运输条件

Room temperature in continental US; may vary elsewhere.
储存方式

Please store the product under the recommended conditions in the Certificate of Analysis.
纯度 & 产品资料
参考文献

AH001 相关分类

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  • Do most proteins show cross-species activity?

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Keywords:

AH0011456769-95-1AH 001AH-001RasHeart failureRhoAGTPasesRhoA-GTPRhoA-RhoGDIαNatural productCardiac fibroblasts.Inhibitorinhibitorinhibit

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