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

Abstract

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 (IC₅₀ = 33.5 nM), which exhibited comparable activity to the clinical candidate CC-90001 (IC₅₀ = 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.

Keywords: Fragment-based drug design; Idiopathic pulmonary fibrosis; Inhibitor; Pyrimidine-2,4-diamine; Structure-activity relationship; Synthesis-accessibility; c-Jun N-Terminal kinase.