Epidermal growth factor receptor (EGFR) is a transmembrane receptor protein in humans. The discovery of activating mutations in EGFR detected in 10% to 30% of patients with non–small cell lung cancer (NSCLC). In addition, it has revolutionized the treatment of this disease. Until recently, EGFR tyrosine kinase inhibitors (TKI), including erlotinib, gefitinib, afatinib, have been the standard-of-care initial therapy for lung cancer. As such, strategies to treat or prevent osimertinib resistance and/or approaches to more effectively inhibit EGFR may lead to improved clinical therapies. Besides, the clinical efficacy of EGFR TKI in EGFR-mutant lung cancer is limited by acquired drug resistance. Thus it highlights the need for alternative strategies to inhibit EGFR. Moreover, we need an inhibitor could augment the efficacy of existing ATP-competitive EGFR inhibitors. JBJ-04-125-02 is a potent, mutant-selective, allosteric and orally active EGFR inhibitor.
JBJ-04-125-02 is a potent, mutant-selective, allosteric and orally active EGFR inhibitor with an IC50 of 0.26 nM for EGFRL858R/T790M. Specifically, JBJ-04-125-02 can inhibit cancer cell proliferation and EGFRL858R/T790M/C797S signaling. Meanwhile, JBJ-04-125-02 has anti-tumor activities. Nonetheless, the combination of osimertinib and JBJ-04-125-02 results in an increase in apoptosis, a more effective inhibition of cellular growth. It has an increased efficacy in vitro and in vivo compared with either single agent alone. Furthermore, JBJ-04-125-02 is effective as a single agent in both in vitro and in vivo models of EGFR-mutant (including C797S) lung cancer. All in all, JBJ-04-125-02 is a potent, mutant-selective, allosteric and orally active EGFR inhibitor with anti-tumor activities.