Discovery of a selective and potent inhibitor of c-Jun N-terminal kinase 1 with anti-pulmonary fibrosis effect

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-11-26 DOI:10.1016/j.bmcl.2024.130044

Shuhua Ren , Fengling Liu , Man Chi , Jinfeng Liu , Yi Huang , Weiwei Huang , Wenjing Gu , Yaxia Yuan , Shurong Hou , Xiabin Chen , Lei Ma

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Abstract

We synthesized and evaluated a series of derivatives based on the pyrimidine-2,4-diamine scaffold as potential JNK1 inhibitors, incorporating bridging rings and spirocyclic modifications to enhance their inhibitory activity. These compounds were biologically assessed through JNK enzyme inhibition assays and Western Blot analysis. Compounds 13, 14 and 19 demonstrated significant inhibitory activity at both the enzyme and cellular level compared to the lead compound 1 and clinical candidate CC-90001. Notably, 14 exhibited strong inhibitory potency against JNK1 with sub-nanomolar efficacy and suppresses TGF-β-induced epithelial-mesenchymal transition, indicating its potential as a promising candidate for further development as an anti-pulmonary fibrosis agent targeting JNK1.

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一种具有抗肺纤维化作用的c-Jun n -末端激酶1选择性有效抑制剂的发现

我们合成并评估了一系列基于嘧啶-2,4-二胺支架的衍生物作为潜在的JNK1抑制剂，结合桥环和螺环修饰以增强其抑制活性。这些化合物通过JNK酶抑制试验和Western Blot分析进行生物学评估。与先导化合物1和临床候选化合物CC-90001相比，化合物13、14和19在酶和细胞水平上均表现出显著的抑制活性。值得注意的是，14对JNK1表现出亚纳摩尔效应的强抑制效力，并抑制TGF-β诱导的上皮-间质转化，表明其有潜力作为靶向JNK1的抗肺纤维化药物进一步开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.