Discovery and development of the preclinical candidate (SH-1092), a potent third generation EGFR inhibitor for the treatment of NSCLC.

Epidermal growth factor receptor (EGFR) is a subclass of tyrosine kinase receptor and it plays an important role in cell growth, proliferation and differentiation in non-small cell lung cancer (NSCLC). Targeting EGFR was proved as an effective approach for the treatment of NSCLC. Herein, we presented the discovery and development of a highly potent and effective EGFR inhibitor, SH-1092 as a potent third generation EGFR inhibitor through cyclization strategy. A methyl group was inserted to the scaffold to finetune the potency and drug-like property. SH-1092 exhibited significant EGFR inhibition with an IC of 0.96 nM and it inhibited H1975 (EGFR T790M/L858R) cell growth at an IC of 8 nM. In addition, it displayed high metabolic stability in vitro and in vivo. Overall, it represents a promising clinical candidate for NSCLC.