Targeted Protein Degradation by Electrophilic PROTACs that Stereoselectively and Site-Specifically Engage DCAF1.
Targeted Protein Degradation by Electrophilic PROTACs that Stereoselectively and Site-Specifically Engage DCAF1.
复制标题
DOI：
10.1021/jacs.2c08964
复制
发表时间：
2022-10-12
影响因子：
15
通讯作者：
Cravatt, Benjamin F.
中科院分区：
文献类型：
--
作者：
Tao, Yongfeng;Remillard, David;Vinogradova, Ekaterina V.;Yokoyama, Minoru;Banchenko, Sofia;Schwefel, David;Melillo, Bruno;Schreiber, Stuart L.;Zhang, Xiaoyu;Cravatt, Benjamin F.
异双功能化合物和分子胶诱导的蛋白质靶向降解为化学探针和药物发现提供了令人兴奋的途径。迄今为止，仅发现了有限数量的E3连接酶的小分子配体，这是实现靶向蛋白质降解的全部潜力的重要限制因素。我们在此报告的氮杂环丁烷丙烯酰胺，立体选择性和位点特异性反应的E3连接酶底物受体DCAF1的半胱氨酸（C1113）的化学蛋白质组学的发现。我们证明了DCAF1的氮杂环丁烷丙烯酰胺配体可以发展成亲电PROTAC（蛋白水解靶向嵌合体），介导人类细胞中的靶向蛋白质降解。我们表明，这一过程是立体选择性的，并没有发生在细胞中表达的C1113A突变体的DCAF1。机制研究表明，仅需要低比例的DCAF1参与来支持亲电PROTAC的蛋白质降解。这些发现，结合在一起，证明了如何立体化学定义的亲电化合物集的化学蛋白质组学分析可以发现支持靶向蛋白质降解的E3连接酶上的可配位位点。
Targeted protein degradation induced by heterobifunctional compounds and molecular glues presents an exciting avenue for chemical probe and drug discovery. To date, small-molecule ligands have been discovered for only a limited number of E3 ligases, which is an important limiting factor for realizing the full potential of targeted protein degradation. We report herein the discovery by chemical proteomics of azetidine acrylamides that stereoselectively and site-specifically react with a cysteine (C1113) in the E3 ligase substrate receptor DCAF1. We demonstrate that the azetidine acrylamide ligands for DCAF1 can be developed into electrophilic PROTACs (proteolysis-targeting chimeras) that mediated targeted protein degradation in human cells. We show that this process is stereoselective and does not occur in cells expressing a C1113A mutant of DCAF1. Mechanistic studies indicate that only low fractional engagement of DCAF1 is required to support protein degradation by electrophilic PROTACs. These findings, taken together, demonstrate how the chemical proteomic analysis of stereochemically defined electrophilic compound sets can uncover ligandable sites on E3 ligases that support targeted protein degradation.
登录
查看更多内容
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Li W;You L;Cooper J;Schiavon G;Pepe-Caprio A;Zhou L;Ishii R;Giovannini M;Hanemann CO;Long SB;Erdjument-Bromage H;Zhou P;Tempst P;Giancotti FG
通讯作者：
Giancotti FG
影响因子：
5.3
作者：
McCall, Chad M.;de Marval, Paula L. Miliani;Xiong, Yue
通讯作者：
Xiong, Yue
影响因子：
14.8
作者：
Bondeson DP;Mares A;Smith IE;Ko E;Campos S;Miah AH;Mulholland KE;Routly N;Buckley DL;Gustafson JL;Zinn N;Grandi P;Shimamura S;Bergamini G;Faelth-Savitski M;Bantscheff M;Cox C;Gordon DA;Willard RR;Flanagan JJ;Casillas LN;Votta BJ;den Besten W;Famm K;Kruidenier L;Carter PS;Harling JD;Churcher I;Crews CM
通讯作者：
Crews CM
DOI：
10.1146/annurev-pharmtox-010715-103507
发表时间：
2017-01-06
影响因子：
12.5
作者：
Bondeson DP;Crews CM
通讯作者：
Crews CM