Abstract B076: Discovery of BBT-176 as fourth generation EGFR tyrosine kinase inhibitor

Abstract

Abstract 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, upon treatment with third-generation EGFR TKIs (Osmertinib) develops C797S resistance[KS1] [u2] in the 20 – 30% of the patients. To date, there is no approved drug for third-generation resistance NSCLC patients. There is an unmet medical need to develop fourth generation EGFR TKIs[KS3] targeting C797S mutation. Extensive structure–activity relationship (SAR) studies led to the discovery of BBT-176 as a reversible fourth generation EGFR TKI. BBT-176 shows promising results with highly potent and anti-cancer efficacy in Osmertinib-resistant in vitro and in vivo cell lines. In mouse models, BBT-176 exhibited potent inhibition of tumor growth, leading to tumor regression in certain cases. Furthermore, promising results were observed in the clinical trial, where two patients with EGFR Del[KS4] 19/T790M/C797S mutations in their blood demonstrated tumor shrinkage and improvements in radiological assessments. BBT-176, a fourth-generation EGFR inhibitor, demonstrates significant preclinical activity against non-small cell lung cancer (NSCLC) that is resistant to current EGFR tyrosine kinase inhibitors (TKIs). This promising compound has shown early signs of clinical efficacy and safety in initial trials. Citation Format: Krishna Babu Duggirala, Kwangho Lee. Discovery of BBT-176 as fourth generation EGFR tyrosine kinase inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B076.