泛素连接酶
连接器
雌激素受体
酰肼
生物
小分子
化学
配体(生物化学)
靶蛋白
DNA连接酶
药物发现
蛋白质水解
受体
组合化学
计算生物学
生物化学
泛素
癌症
遗传学
计算机科学
乳腺癌
有机化学
酶
操作系统
基因
作者
Brett L Roberts,Zewei Ma,Ang Gao,Eric D Leisten,Dan Yin,Wei Xu,Weiping Tang
标识
DOI:10.1021/acschembio.0c00140
摘要
Proteolysis targeting chimeras (PROTACs) have emerged as useful chemical probes and potential therapeutics by taking advantage of the ubiquitin–proteasome system to degrade intracellular disease-associated proteins. PROTACs are heterobifunctional molecules composed of a target protein ligand, E3 ubiquitin ligase ligand, and a linker between them. The generation of efficient PROTACs requires screening of many parameters, especially the lengths and types of the linkers. We report our proof-of-concept study using a two-stage strategy to facilitate the development of PROTACs against the estrogen receptor (ER). In stage one, a library of close to 100 PROTACs was synthesized by simply mixing a library of ERα ligands containing a hydrazide functional group at different positions with a preassembled library of E3 ligase ligands bearing different types and lengths of linkers with a terminal aldehyde group in a 1:1 ratio. Cell-based screening occurred without further purification, because the formation of the acylhydrazone linkage is highly efficient and produces water as the only byproduct. Compound A3 was the most potent ER degrader in two ER+ cell lines (DC50= ∼ 10 nM, Dmax= ≥ 95%). Stage two involved transformation to a more stable amide linker to generate a more drug-like molecule. The new compound, AM-A3, showed comparable biological activity (DC50 = 1.1 nM, Dmax = 98%) and induced potent antiproliferation (IC50= 13.2 nM, Imax= 69%) in MCF-7. This proof-of -concept study demonstrates that the two-stage strategy can significantly facilitate the development of PROTACs against ER without the tedious process of making large numbers of PROTACs one by one. It has the potential to be expanded to many other targets.
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