HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of Halo Tag Fusion Proteins

被引：333

作者：

Buckley, Dennis L. ^{[1
]}

Raina, Kanak ^{[1
]}

Darricarrere, Nicole ^{[2
]}

Hines, John ^{[2
]}

Gustafson, Jeffrey L. ^{[1
]}

Smith, Ian E. ^{[4
]}

Miah, Aija H. ^{[4
]}

Harling, John D. ^{[4
]}

Crews, Craig M. ^{[1
,2
,3
]}

机构：

[1] Yale Univ, Dept Chem, New Haven, CT 06520 USA

[2] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA

[3] Yale Univ, Dept Pharmacol, New Haven, CT 06520 USA

[4] GlaxoSmithKline, Prot Degradat Discovery Performance Unit, Stevenage SG1 2NY, Herts, England

来源：

ACS CHEMICAL BIOLOGY | 2015年 / 10卷 / 08期

基金：

美国国家卫生研究院;

关键词：

TARGETED DEGRADATION; PROTEASOME INHIBITOR; LIVING CELLS; CANCER; UBIQUITINATION; ACTIVATION; KNOCKDOWN; TOOL; ANTAGONISTS; EPOXOMICIN;

D O I：

10.1021/acschembio.5b00442

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 knock down widely used HaloTag7 fusion proteins in a general fashion.

引用

收藏

页码：1831 / 1837

页数：7

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