Discovery of BBT-176 as a fourth-generation EGFR tyrosine kinase inhibitor

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) improve overall survival rate in patients with EGFR mutated non-small cell lung cancers (NSCLC). However, treatment with third-generation EGFR TKIs (osimertinib) develops C797S resistance in 20–30 % of the patients. To date, there is no approved drug for third-generation resistant EGFR-mutant NSCLC patients. There is an urgent unmet medical need to develop fourth-generation EGFR TKIs targeting C797S containing mutations. Extensive structure–activity relationship (SAR) studies led to the discovery of BBT-176 as a “first-in-class” reversible fourth-generation EGFR TKI. BBT-176 shows promising results of potent anti-cancer efficacy in osimertinib-resistant cell lines. In patient-derived cell (PDC) models, BBT-176 exhibits tumor regression once-daily oral 100 mg/kg dose as a single agent in day 25.