Structure-activity relationships of novel quinazoline derivatives with high selectivity for HER2 over EGFRStructure–activity relationships of novel quinazoline derivatives with high selectivity for HER2 over EGFR
- Authors
- Lee, Jung Wuk; Choi, Changyu; Kim, Jihyung; Lee, Sohee; Kim, Jina; Lee, Yoonji; Min, Kyung Hoon
- Issue Date
- Mar-2022
- Publisher
- PHARMACEUTICAL SOC KOREA
- Keywords
- HER2; EGFR; Quinazoline; Selectivity; Kinase inhibitor; Cancer
- Citation
- ARCHIVES OF PHARMACAL RESEARCH, v.45, no.3, pp 123 - 141
- Pages
- 19
- Journal Title
- ARCHIVES OF PHARMACAL RESEARCH
- Volume
- 45
- Number
- 3
- Start Page
- 123
- End Page
- 141
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/57673
- DOI
- 10.1007/s12272-022-01376-4
- ISSN
- 0253-6269
1976-3786
- Abstract
- The gene amplification of human epidermal growth factor receptor 2 (HER2) plays an essential role in the proliferation and progression of several cancers. However, HER2 inhibitors such as lapatinib strongly suppress wild-type EGFR, resulting in severe adverse effects. Therefore, there is an unmet need for highly selective HER2 inhibitors. In this study, we describe the design and synthesis of novel quinazoline derivatives that exhibit enhanced selectivity for HER2 over wild-type EGFR. Structure-activity relationship analysis indicated that the selectivity for HER2 over EGFR depends on the aniline moiety at C-4 and the substituents at C-6 in the quinazoline derivatives. Compound 7c with an IC50 of 8 nM for HER2 exhibited significantly higher selectivity for HER2 over EGFR, with a 240-fold improvement over lapatinib. In addition, the synthesized compounds exhibited anti-proliferative activity in the nanomolar range against SKBR3, a human breast cancer cell line that overexpresses HER2.
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Collections - Graduate School > ETC > 1. Journal Articles
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