Design, synthesis and biological evaluation of new bivalent quinazoline analogues as IAP antagonists
- Authors
- Bae, Inhwan; Kim, Daejin; Choi, Jaeyul; Kim, Jisook; Kim, Minjeong; Park, Bokyung; Kim, Young Hoon; Ahn, Young Gil; Kim, Ha Hyung; Kim, Dae Kyong
- Issue Date
- 15-Feb-2021
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- IAP antagonist; BIR3; Apoptosis; SMAC mimetics; Bivalent
- Citation
- BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, v.34
- Journal Title
- BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
- Volume
- 34
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/48082
- DOI
- 10.1016/j.bmcl.2020.127676
- ISSN
- 0960-894X
1464-3405
- Abstract
- We recently reported the biological evaluations of monovalent IAP antagonist 7 with good potency (MDA-MB-231, IC50 = 19 nM). In an effort to increase cellular activity and improve favorable drug-like properties, we newly designed and synthesized bivalent analogues based on quinazoline structure of 7. Optimization of cellular potency and CYP inhibition led to the identification of 27, which showed dramatic increase of over 100-fold (IC50 = 0.14 nM) and caused substantial tumor regressions in MDA-MB-231 xenograft model. These results strongly support 27 as a promising bivalent antagonist for the development of an effective anti-tumor approaches.
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Collections - College of Pharmacy > School of Pharmacy > 1. Journal Articles
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