HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins.
HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins.
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DOI：
10.1021/acschembio.5b00442
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发表时间：
2015-08-21
影响因子：
4
通讯作者：
Crews CM
中科院分区：
文献类型：
--
作者：
Buckley DL;Raina K;Darricarrere N;Hines J;Gustafson JL;Smith IE;Miah AH;Harling JD;Crews CM
小分子诱导的蛋白质降解是发展化学探针的一个有吸引力的策略。诱导靶向蛋白降解的一种方法涉及使用PROTACs，这是一种异双功能分子，可以招募特定的E3连接酶到感兴趣的蛋白质上。PROTACs已经成功地用于降解细胞中的许多蛋白质，但是在之前的PROTACs中使用的肽类E3连接酶配体阻碍了它们向更成熟的化学探针或治疗方法的发展。我们报道了一种新型PROTACs的设计，它结合了小分子VHL配体来成功地降解HaloTag7融合蛋白。这些HaloPROTACs将激发未来具有更多类似药物性质的PROTACs的发展。此外，这些HaloPROTACs是有用的化学遗传工具，因为它们能够以一般方式化学敲除广泛使用的HaloTag7融合蛋白。
Small molecule-induced protein degradation is an attractive strategy for the development of chemical probes. One method for inducing targeted protein degradation involves the use of PROTACs, heterobifunctional molecules that can recruit specific E3 ligases to a desired protein of interest. PROTACs have been successfully used to degrade numerous proteins in cells, but the peptidic E3 ligase ligands used in previous PROTACs have hindered their development into more mature chemical probes or therapeutics. We report the design of a novel class of PROTACs that incorporate small molecule VHL ligands to successfully degrade HaloTag7 fusion proteins. These HaloPROTACs will inspire the development of future PROTACs with more drug-like properties. Additionally, these HaloPROTACs are useful chemical genetic tools, due to their ability to chemically knockdown widely used HaloTag7 fusion proteins in a general fashion.