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Discovery of a novel DDRs kinase inhibitor XBLJ-13 for the treatment of idiopathic pulmonary fibrosis

文献类型：期刊论文

作者Dong, Ying2,3; Tang, Bi-xi2,3,4; Wang, Qi1,3; Zhou, Li-wei1,5,6; Li, Cong2; Zhang, Xuan2,3; Sun, Dan-dan7; Sun, Xin8; Zhang, Xue-mei4; Xiong, Bing1,3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2021-11-24
页码11
关键词idiopathic pulmonary fibrosis DDRs kinase inhibitor indazole derivatives XBLJ-13 nintedanib bleomycin-induced pulmonary fibrosismouse model
ISSN号1671-4083
DOI10.1038/s41401-021-00808-z
通讯作者Chen, Dan-qi(dqchen@simm.ac.cn) ; Zang, Yi(Yzang@simm.ac.cn)
英文摘要Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease characterized by destruction of lung parenchyma and deposition of extracellular matrix in interstitial and alveolar spaces. But known drugs for IPF are far from meeting clinical demands, validation of drug targets against pulmonary fibrosis is in urgent demand. Tyrosine kinase receptor DDRs has been considered as a potential therapeutic target for pulmonary fibrosis due to its pathological collagen binding property and the roles in regulating extracellular matrix remodeling. In this study we designed and synthesized a new indazole derivative XBLJ-13, and identified XBLJ-13 as a highly specific and potent DDRs inhibitor with anti-inflammation and anti-fibrosis activities. We first demonstrated that DDR1/2 was highly expressed in the lung tissues of IPF patients. Then we showed that XBLJ-13 potently inhibited DDR1 and DDR2 kinases with IC50 values of 17.18 nM and 15.13 nM, respectively. Among a panel of 34 kinases tested, XBLJ-13 displayed relatively high selectivity for DDRs with minimal inhibitory effect on PDGFR family and FGFR1, as well as Abl kinase that had high homology with DDRs. Extensive profiling of XBLJ-13 revealed that the new inhibitor had much lower toxicity than nintedanib and better pharmacokinetic properties in mice. Furthermore, pharmacodynamic evaluation conducted in bleomycin-induced pulmonary fibrosis mice showed that administration of XBLJ-13 (30, 60, 90 mg center dot kg(-1)center dot d(-1), i.g.) for 12 days significantly and dose-dependently ameliorated lung inflammation and fibrosis. Together, this study confirms that DDRs kinase is a potential target for PF, Particularly, compound XBLJ-13 is a highly potent and specific DDRs inhibitor, along with good pharmacokinetics profiles, and preferable in vivo efficacy, suggesting that it is a potential candidate for the treatment of PF.
WOS关键词ACTIVATION ; MACROPHAGES ; MECHANISMS ; MICE
资助项目National Natural Science Foundation of China[81773779] ; National Natural Science Foundation of China[81125023] ; National Natural Science Foundation of China[U1703235] ; National Natural Science Foundation of China[31871414] ; National Natural Science Foundation of China[81701220] ; Shanghai Science and Technology Development Funds[19JC1416300] ; Shanghai Science and Technology Development Funds[18431907100] ; Key New Drug Creation and Manufacturing Program of China[2019ZX09201001-004-010] ; Key New Drug Creation and Manufacturing Program of China[2019ZX09201001-003-010] ; Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-004-009] ; Shanghai Aging and Maternal and Child Health Research Program[2020yjzx0136] ; Backbone Program of Shanghai Pulmonary Hospital[fkgg1809] ; K. C. Wong Education Foundation
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000722085200001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/298967]  
专题新药研究国家重点实验室
通讯作者Chen, Dan-qi; Zang, Yi
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China
5.Shanghai Univ, Coll Sci, Ctr Supramol Chem & Catalysis, Shanghai 200444, Peoples R China
6.Shanghai Univ, Coll Sci, Dept Chem, Shanghai 200444, Peoples R China
7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
8.Henan Univ, Sch Pharm, Kaifeng 475004, Peoples R China
9.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, Qingdao 266237, Peoples R China
10.UCAS, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Dong, Ying,Tang, Bi-xi,Wang, Qi,et al. Discovery of a novel DDRs kinase inhibitor XBLJ-13 for the treatment of idiopathic pulmonary fibrosis[J]. ACTA PHARMACOLOGICA SINICA,2021:11.
APA Dong, Ying.,Tang, Bi-xi.,Wang, Qi.,Zhou, Li-wei.,Li, Cong.,...&Zang, Yi.(2021).Discovery of a novel DDRs kinase inhibitor XBLJ-13 for the treatment of idiopathic pulmonary fibrosis.ACTA PHARMACOLOGICA SINICA,11.
MLA Dong, Ying,et al."Discovery of a novel DDRs kinase inhibitor XBLJ-13 for the treatment of idiopathic pulmonary fibrosis".ACTA PHARMACOLOGICA SINICA (2021):11.

入库方式： OAI收割

来源：上海药物研究所

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