Abstract
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·kg−1·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.
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Acknowledgements
This study was supported by National Natural Science Foundation of China (No. 81773779, 81125023, U1703235, 31871414, and 81701220), Shanghai Science and Technology Development Funds (19JC1416300 and 18431907100), Key New Drug Creation and Manufacturing Program of China (2019ZX09201001–004–010, 2019ZX09201001–003–010, and 2018ZX09711002–004–009), Shanghai Aging and Maternal and Child Health Research Program (2020yjzx0136), Backbone Program of Shanghai Pulmonary Hospital (fkgg1809) and K. C. Wong Education Foundation.
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YD and BXT contributed equally, and they performed biological experiments and drafted the manuscript. DQC, QW and LWZ performed the chemical synthesis. CL performed the kinome selectivity assay. XZ, DDS and XS helped with the animal experiments. HS provided the human lung tissues. YZ, DQC, BX, XMZ and JL corrected the manuscript and directed the study. All authors have given approval to the final version of the manuscript.
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Dong, Y., Tang, Bx., Wang, Q. et al. Discovery of a novel DDRs kinase inhibitor XBLJ-13 for the treatment of idiopathic pulmonary fibrosis. Acta Pharmacol Sin 43, 1769–1779 (2022). https://doi.org/10.1038/s41401-021-00808-z
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DOI: https://doi.org/10.1038/s41401-021-00808-z
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