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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| Format: | Article |
| Language: | English |
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Elsevier
2025-07-01
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| Series: | Results in Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211715625003893 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Krishna Babu Duggirala |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9e6d9d26b7294e02b8f7e3dbe502d4ec |
| institution | DOAJ |
| issn | 2211-7156 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Results in Chemistry |
| spelling | doaj-art-9e6d9d26b7294e02b8f7e3dbe502d4ec2025-08-20T03:01:46ZengElsevierResults in Chemistry2211-71562025-07-011610240610.1016/j.rechem.2025.102406Discovery of BBT-176 as a fourth-generation EGFR tyrosine kinase inhibitorKrishna Babu Duggirala0Hyeonjeong Choe1Byeong Uk Jeon2Chaewon Park3Jiyeun Yoon4Hwan Kim5Myoung Eun Jung6Gildon Choi7Chong Hak Chae8Byoung Chul Cho9Kwangho Lee10Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South KoreaBio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South KoreaBio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South KoreaYonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South KoreaYonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South KoreaYonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South KoreaBio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South KoreaBio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Medicinal Chemistry & Pharmacology, Korea National University of Science & Technology, Daejeon 34113, South Korea; Corresponding author at: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Corresponding authors.Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea; Corresponding authors.Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Medicinal Chemistry & Pharmacology, Korea National University of Science & Technology, Daejeon 34113, South Korea; Corresponding author at: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.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.http://www.sciencedirect.com/science/article/pii/S2211715625003893EGFR-TKIsEGFR Del19/C797SEGFR Del19/T790M/C797SNSCLCBBT-176 |
| spellingShingle | 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 Discovery of BBT-176 as a fourth-generation EGFR tyrosine kinase inhibitor Results in Chemistry EGFR-TKIs EGFR Del19/C797S EGFR Del19/T790M/C797S NSCLC BBT-176 |
| title | Discovery of BBT-176 as a fourth-generation EGFR tyrosine kinase inhibitor |
| title_full | Discovery of BBT-176 as a fourth-generation EGFR tyrosine kinase inhibitor |
| title_fullStr | Discovery of BBT-176 as a fourth-generation EGFR tyrosine kinase inhibitor |
| title_full_unstemmed | Discovery of BBT-176 as a fourth-generation EGFR tyrosine kinase inhibitor |
| title_short | Discovery of BBT-176 as a fourth-generation EGFR tyrosine kinase inhibitor |
| title_sort | discovery of bbt 176 as a fourth generation egfr tyrosine kinase inhibitor |
| topic | EGFR-TKIs EGFR Del19/C797S EGFR Del19/T790M/C797S NSCLC BBT-176 |
| url | http://www.sciencedirect.com/science/article/pii/S2211715625003893 |
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