Catalytic in vivo protein knockdown by small-molecule PROTACs.
Catalytic in vivo protein knockdown by small-molecule PROTACs.
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DOI：
10.1038/nchembio.1858
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发表时间：
2015-08
影响因子：
14.8
通讯作者：
Crews CM
中科院分区：
文献类型：
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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
目前占主导地位的治疗范式是基于最大化药物受体占有率以实现临床益处。然而，这一策略通常需要过高的药物浓度来确保足够的占有率，往往会导致不良副作用。在这里，我们描述了蛋白质水解靶向嵌合体(PROTACs)方法的主要改进，这是一种化学敲除策略，在这种策略中，一个异双功能分子将特定的蛋白质靶标招募到E3泛素连接酶上，导致靶标的泛素化和降解。这些化合物的催化作用在于它们能够诱导超化学计量比的蛋白质泛素化，提供不受平衡占有率限制的效力。我们提出了两种PROTAC，能够在纳摩尔浓度下将蛋白质水平具体降低90%。此外，小鼠研究表明，它们在肿瘤异种移植中提供了广泛的组织分布和靶向蛋白的击倒。总之，这些数据显示了一种蛋白质敲除系统，该系统结合了小分子制剂的许多有利性质与RNAi和CRISPR的强大蛋白质敲除系统。
The current predominant theapeutic paradigm is based on maximizing drug-receptor occupancy to achieve clinical benefit. This strategy, however, generally requires excessive drug concentrations to ensure sufficient occupancy, often leading to adverse side effects. Here, we describe major improvements to the proteolysis targeting chimeras (PROTACs) method, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target’s ubiquitination and degradation. These compounds behave catalytically in their ability to induce the ubiquitination of super-stoichiometric quantities of proteins, providing efficacy that is not limited by equilibrium occupancy. We present two PROTACs that are capable of specifically reducing protein levels by >90% at nanomolar concentrations. In addition, mouse studies indicate that they provide broad tissue distribution and knockdown of the targeted protein in tumor xenografts. Together, these data demonstrate a protein knockdown system combining many of the favorable properties of small-molecule agents with the potent protein knockdown of RNAi and CRISPR.