Structure-Guided Development of Dual Inhibitors of EGFR and JNK to Treat GBM and NSCLC

Abstract

Abnormal epidermal growth factor receptor (EGFR) signaling is widespread in cancer, making the EGFR as an important target for therapy. The third-generation EGFR small-molecule inhibitors are at the forefront clinically for treatment of patients with non-small cell lung cancer (NSCLC). However, acquired resistance limits the effectiveness. The c-Jun N-terminal kinase (JNK) signaling axis mediates primary resistance to EGFR inhibition in glioblastoma (GBM) and NSCLC. Therefore, it's a new approach of using a dual EGFR and JNK inhibition to treat EGFR-expressing GBM and NSCLC is a new approach. On the basis of an iterative approach of docking, two series of trisubstituted 1,2,4-triazoles and thiazoles were designed and synthesized. Some compounds demonstrated inhibitory activity for EGFR and JNK kinases with IC50 values in the low nanomolar range. This work may lead to design and optimize the potent EGFR and JNK inhibitors in the future.