A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader

被引：311

作者：

Huang, Hai-Tsang ^{[1
,2
]}

Dobrovolsky, Dennis ^{[1
,2
]}

Paulk, Joshiawa ^{[3
]}

Yang, Guang ^{[3
,4
]}

Weisberg, Ellen L. ^{[3
]}

Doctor, Zainab M. ^{[1
,2
]}

Buckley, Dennis L. ^{[3
]}

Cho, Joong-Heui ^{[5
]}

Ko, Eunhwa ^{[5
]}

Jang, Jaebong ^{[1
,2
]}

Shi, Kun ^{[7
,8
]}

Choi, Hwan Geun ^{[5
]}

Griffin, James D. ^{[3
,6
]}

Li, Ying ^{[7
]}

Treon, Steven P. ^{[3
,4
,6
]}

Fischer, Eric S. ^{[1
,2
]}

Bradner, James E. ^{[3
,6
]}

Tan, Li ^{[1
,2
,7
]}

Gray, Nathanael S. ^{[1
,2
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[2] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[4] Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA

[5] Daegu Gyeongbuk Med Innovat Fdn, New Drug Dev Ctr, Daegu 41061, South Korea

[6] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[7] Chinese Acad Sci, Shanghai Inst Organ Chem, Interdisciplinary Res Ctr Biol & Chem, Shanghai 201210, Peoples R China

[8] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

来源：

CELL CHEMICAL BIOLOGY | 2018年 / 25卷 / 01期

关键词：

E3 UBIQUITIN LIGASE; ACUTE MYELOID-LEUKEMIA; BRUTONS TYROSINE KINASE; SMALL MOLECULES; PROTEIN-DEGRADATION; FLT3; MUTATIONS; INHIBITOR; TARGET; COMPLEX; DESIGN;

D O I：

10.1016/j.chembiol.2017.10.005

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：

Heterobifunctional molecules that recruit E3 ubiquitin ligases, such as cereblon, for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein targets. In this study, we designed a multi-kinase degrader by conjugating a highly promiscuous kinase inhibitor with a cereblon-binding ligand, and used quantitative proteomics to discover 28 kinases, including BTK, PTK2, PTK2B, FLT3, AURKA, AURKB, TEC, ULK1, ITK, and nine members of the CDK family, as degradable. This set of kinases is only a fraction of the intracellular targets bound by the degrader, demonstrating that successful degradation requires more than target engagement. The results guided us to develop selective degraders for FLT3 and BTK, with potentials to improve disease treatment. Together, this study demonstrates an efficient approach to triage a gene family of interest to identify readily degradable targets for further studies and pre-clinical developments.

引用

页码：88 / +

页数：18

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