Wang Qi, Tang Bixi, Sun Dandan, Dong Ying, Ji Yinchun, Shi Huanyu, Zhou Liwei, Yang Yueyue, Luo Menglan, Tan Qian, Chen Lin, Dong Yue, Li Cong, Xie Rongrong, Zang Yi, Shen Jingkang, Xiong Bing, Li Jia, Chen Danqi
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Acta Pharm Sin B. 2022 Apr;12(4):1943-1962. doi: 10.1016/j.apsb.2021.11.012. Epub 2021 Nov 17.
Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with a median survival time of 3-5 years. Inaccurate diagnosis, limited clinical therapy and high mortality together indicate that the development of effective therapeutics for IPF is an urgent need. In recent years, it was reported that DDRs are potential targets in anti-fibrosis treatment. Based on previous work we carried out further structure modifications and led to a more selective inhibitor by averting some fibrosis-unrelated kinases, such as RET, AXL and ALK. Extensive profiling of compound has demonstrated that it has potent DDR1/2 inhibitory activities, low toxicity, good pharmacokinetic properties and reliable anti-fibrosis efficacy. Therefore, we confirmed that discoidin domain receptors are promising drug targets for IPF, and compound would be a promising candidate for further drug development.
特发性肺纤维化（IPF）是一种慢性致命性肺部疾病，中位生存时间为3至5年。诊断不准确、临床治疗有限以及高死亡率共同表明，迫切需要开发针对IPF的有效治疗方法。近年来，有报道称盘状结构域受体（DDRs）是抗纤维化治疗的潜在靶点。基于我们之前的工作，我们进一步进行了结构修饰，通过避开一些与纤维化无关的激酶，如RET、AXL和ALK，得到了一种更具选择性的抑制剂。对该化合物的广泛分析表明，它具有强大的DDR1/2抑制活性、低毒性、良好的药代动力学特性和可靠的抗纤维化疗效。因此，我们证实盘状结构域受体是IPF有前景的药物靶点，该化合物将是进一步药物开发的有前景的候选物。
