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Synthesis-accessibility-oriented design of c-Jun N-terminal kinase 1 inhibitor

Hewen Qian,Yuanqing Ding,Xingyu Deng,Weiwei Huang,Zhenzhen Li,Fengling Liu,Jie Zhang,Lihui Wang,Junping Liu,Yaxia Yuan,Shurong Hou,Xiabin Chen,Lei Ma

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disease with poor prognosis and limited treatment options. The c -Jun N-Terminal Kinase 1 (JNK1), a key component of the MAPK pathway, has been implicated in the pathogenesis of IPF and represents a potential therapeutic target. However, the development of JNK1 inhibitors has been slowed, partly due to synthetic complexity in medicinal chemistry modification. Here, we report a synthesis-accessibility-oriented strategy for designing JNK1 inhibitors based on computational prediction of synthetic feasibility and fragment-based molecule generation. This strategy led to the discovery of several potent JNK1 inhibitors, such as compound C6 (IC 50  = 33.5 nM), which exhibited comparable activity to the clinical candidate CC-90001 (IC 50  = 24.4 nM). The anti-fibrotic effect of C6 was further confirmed in animal model of pulmonary fibrosis . Moreover, compound C6 could be synthesized in only two steps, compared to nine steps for CC-90001 . Our findings suggest that compound C6 is a promising lead for further optimization and development as a novel anti-fibrotic agent targeting JNK1. In addition, the discovery of C6 also demonstrates the feasibility of synthesis-accessibility-oriented strategy in lead discovery.