Yeon Ju Kim, Myoung Eun Jung, Ju Yeong Lee, Yun-Han Lee, Gildon Choi, Moon-Kook Jeon
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Synthesis and biological evaluation of (2-aminosulfonylpyridin-6-yl)pyrazolopyrimidinone derivatives as Wee1 inhibitors for cancer treatment
For an analog-based design of novel Wee1 inhibitors, we profiled in vitro ADMET and in vivo PK properties of adavosertib. Based on the properties of adavosertib, we aimed to improve its metabolic stability by designing a novel target compound 1a with an aminosulfonyl group instead of the 2-hydroxypropan-2-yl moiety in adavosertib. Derivatives of target compound 1a were synthesized and evaluated for Wee1 enzyme inhibition and liver microsomal phase I stability. We identified compound 1a as a sub-nanomolar Wee1 inhibitor and 10 additional compounds with one-digit nanomolar Wee1 inhibitory activity, among which seven compounds including 1a exhibited improved metabolic stabilities compared with adavosertib. However, MDA-MB-231 cell growth inhibitory activities of all synthesized compounds and Wee1 substrate phosphorylation inhibitory activities of selected compounds were inferior to adavosertib overall. Moreover, the representative compound 1a exhibited low permeability, which may be the reason for the low cellular activities of compound 1a.
期刊介绍:
The Bulletin of the Korean Chemical Society is an official research journal of the Korean Chemical Society. It was founded in 1980 and reaches out to the chemical community worldwide. It is strictly peer-reviewed and welcomes Accounts, Communications, Articles, and Notes written in English. The scope of the journal covers all major areas of chemistry: analytical chemistry, electrochemistry, industrial chemistry, inorganic chemistry, life-science chemistry, macromolecular chemistry, organic synthesis, non-synthetic organic chemistry, physical chemistry, and materials chemistry.