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

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, t...

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Main Authors: Krishna Babu Duggirala, Hyeonjeong Choe, Byeong Uk Jeon, Chaewon Park, Jiyeun Yoon, Hwan Kim, Myoung Eun Jung, Gildon Choi, Chong Hak Chae, Byoung Chul Cho, Kwangho Lee
Format: Article
Language:English
Published: Elsevier 2025-07-01
Series:Results in Chemistry
Subjects:
EGFR-TKIs
EGFR Del19/C797S
EGFR Del19/T790M/C797S
NSCLC
BBT-176
Online Access:http://www.sciencedirect.com/science/article/pii/S2211715625003893
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Summary: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.
ISSN:2211-7156

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