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

Bioorg Med Chem Lett

Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address:

Published: February 2025

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Article 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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http://dx.doi.org/10.1016/j.bmcl.2024.130044DOI Listing

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