MOLECULES
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2018
·Vol. 23
·期 12
·3369
·
IF 3.098
Li-Min Zhao,Zhen Guo,Yi-Jie Xue,Jun Zhe Min,Wen-Jing Zhu,Xiang-Yu Li,Hu-Ri Piao,Cheng Hua Jin
The transforming growth factor-β (TGF-β), in which overexpression has been associated with various diseases, has become an attractive molecular target for the treatment of cancers. Thirty-two quinoxaline-derivatives of 3-substituted-4-(quinoxalin-6-yl) pyrazoles14a–d,15a–d,16a–d,17a–d,18a–d,19a–d,25a,25b,25d,26a,26b,26d,27b, and27dwere synthesized and evaluated for their activin TGF-β type I receptor kinase and p38α mitogen activated protein (MAP) kinase inhibitory activity in enzymatic assays. Among these compounds, the most active compound19binhibited TGF-β type I receptor kinase phosphorylation with an IC50value of 0.28 µM, with 98% inhibition at 10 µM. Compound19balso had good selectivity index of >35 against p38α MAP kinase, with 9.0-fold more selective than clinical candidate, compound3(LY-2157299). A molecular docking study was performed to identify the mechanism of action of the synthesized compounds and their good binding interactions were observed. ADMET prediction of good active compounds showed that these ones possess good pharmacokinetics and drug-likeness behavior.Keywords:TGF-β;ALK5 inhibitor;kinase assay;selectivity;docking
研究领域:
药理学
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分子生物学
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药物化学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2024
·
IF 6
Yu-Qing Meng,Jie Ren,Jing-Xin Sun,Fang-Yan Guo,Jun-Zhe Min,Ji-Xing Nan,Ji-Shan Quan,Li-Hua Lian,Cheng-Hua Jin
Four series of imidazoles ( 15a – g , 20c , and 20d ) and thiazoles ( 18a – g , 22a , and 22b ) possessing various amino acids were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) inhibitory activities in an enzymatic assay. Among them, compounds 15g and 18c showed the highest inhibitory activity against ALK5, with IC 50 values of 0.017 and 0.025 μM, respectively. Compounds 15g and 18c efficiently inhibited extracellular matrix (ECM) deposition in TGF-β-induced hepatic stellate cells (HSCs), and eventually suppressed HSC activation. Moreover, compound 15g showed a good pharmacokinetic (PK) profile with a favorable half-life (t 1/2 = 9.14 h). The results indicated that these compounds exhibited activity targeting ALK5 and may have potential in the treatment of liver fibrosis; thus they are worthy of further study.
研究领域:
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR DIVERSITY
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2024
·
IF 3.9
Ding Shu-Yan,Yang Yu-Xuan,Liu Chuang,Quan Xu-Yin,Zhao Zi-Han,Jin Cheng-Hua
Four series of sulfonamide derivatives ( 13a – b , 14a – d , 15a – b , and 16a – d ) were synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) inhibitory activities. Of these, compounds 13b (IC 50 = 0.130 μM) and 15a (IC 50 = 0.130 μM) showed the highest inhibitory activities against ALK5 kinase, with activities similar to the positive control LY - 2157299 . Notably, we discovered that introduction of sulfonamide group at the 2-position of the central imidazole ring significantly increased ALK5 inhibitory activity. Compounds 13b and 15a did not show toxicity in A549 cells up to the maximum concentration of 50 μM, and effectively inhibited TGF-β1-induced Smad-signaling and cell motility in A549 cells. The results indicate that compounds 13b and 15a are worth of further development as anticancer agents.
研究领域:
药物化学
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分子生物学
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Xue-Li Jiang,Chuang Liu,Zi-Ying Zhan,Xiao-Qi Lan,Yan-Ling Wu,Ji-Xing Nan,Cheng-Hua Jin,Li-Hua Lian
Liver fibrosis is a critical precursor to the progression of cirrhosis and liver cancer. However, the development of precision therapies for this condition has been impeded by incompletely elucidated molecular mechanisms. Activin receptor like kinase 5 (ALK5), termed TGF-β type I receptor (TGF-βRI), has been identified as a promising therapeutic target for antifibrotic drug development. In this study, we designed and synthesized two novel thiazole derivatives (J-1155 and J-1156) featuring enantiomeric amino acid moieties to selectively target ALK5 for hepatic fibrosis treatment. Our data demonstrated that both compounds effectively attenuate hepatic fibrosis and associated inflammation through dual inhibition of the TGF-β/Smad signaling pathway and blockade of the P2X7R-NLRP3 inflammasome axis. In comparison, J-1156 demonstrated superior overall therapeutic efficacy to J-1155 in terms of anti-fibrotic efficacy, while J-1155 exhibited superior modulation of Smurf2. Collectively, our observations demonstrate the potential of J-1155 and J-1156 as dual novel therapeutic agents targeting hepatic fibrosis.
研究领域:
药理学
·
分子生物学
·
肝脏疾病研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COMPOSITES PART B-ENGINEERING
·
2022
·
IF 11.322
Yonghong Fan,Juan Pei,Xinxin Li,Yinhua Qin,Youqian Xu,Ming Ke,Jie Zhang,Yong Liu,Ju Tan,Mingcan Yang,Gang Li,Tianqing Li,Chuhong Zhu
Tissue-engineered vascular grafts (TEVGs) show great potential in clinics for treating vascular diseases. However, the complications including thrombosis, delayed endothelialization , and endothelial-to-mesenchymal transition (EndMT) induced pathological remodeling have been demonstrated to be the main cause of graft failure. Here, we have developed a multifunctional surface by immobilizing ALK5 inhibitor loaded covalent organic framework (COF) nanoparticles , recombinant CD47 protein, and vascular endothelial growth factor (VEGF). Such a surface can prevent thrombosis and stenosis in TEVGs. Immobilization of VEGF facilitated the recruitment of endothelial-forming cells to accelerate endothelialization. Grafting of CD47 endowed the TEVGs with stealth function to inhibit the adhesion and activation of platelets and macrophages, thereby suppressing thrombus formation and reducing the secretion of EndMT triggers (i.e. TNF-α and IL-1β). In addition, long-term in situ delivery of ALK5 inhibitor could block the TGF-β signaling pathway that mediated EndMT to prevent intima hyperplasia and endothelial dysfunction during graft remolding. This synergistic strategy is competent to support the formation of functional endothelium on the neo-intima, and has shown promising preliminary results in keeping the patency of TEVGs.
研究领域:
组织工程
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血管生物学
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生物材料
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免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）