Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development

Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to...

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Published in:Cell Vol. 183; no. 6; p. 1714
Main Authors: Donovan, Katherine A, Ferguson, Fleur M, Bushman, Jonathan W, Eleuteri, Nicholas A, Bhunia, Debabrata, Ryu, SeongShick, Tan, Li, Shi, Kun, Yue, Hong, Liu, Xiaoxi, Dobrovolsky, Dennis, Jiang, Baishan, Wang, Jinhua, Hao, Mingfeng, You, Inchul, Teng, Mingxing, Liang, Yanke, Hatcher, John, Li, Zhengnian, Manz, Theresa D, Groendyke, Brian, Hu, Wanyi, Nam, Yunju, Sengupta, Sandip, Cho, Hanna, Shin, Injae, Agius, Michael P, Ghobrial, Irene M, Ma, Michelle W, Che, Jianwei, Buhrlage, Sara J, Sim, Taebo, Gray, Nathanael S, Fischer, Eric S
Format: Journal Article
Language:English
Published: United States 10.12.2020
Subjects:
Adult
Cell Line
Databases, Protein
Female
Humans
Male
Middle Aged
Proteasome Endopeptidase Complex - metabolism
Protein Kinases - genetics
Protein Kinases - metabolism
Proteolysis
Proteome - metabolism
Proteomics
RNA, Messenger - genetics
RNA, Messenger - metabolism
Ubiquitin-Protein Ligases - metabolism
Young Adult
kinase
E3 ligase
PROTAC
ubiquitin proteasome system
targeted degradation
IMiD
degrader
ubiquitin
ISSN:1097-4172, 1097-4172
Online Access:Get more information
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Summary:Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to a lack of understanding of the relative importance of the key molecular events required to induce target degradation. Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive dataset provides chemical leads for ∼200 kinases and demonstrates that the current practice of starting from the highest potency binder is an ineffective method for discovering active compounds. We develop multitargeted degraders to answer fundamental questions about the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent. This work will not only fuel kinase degrader discovery, but also provides a blueprint for evaluating targeted degradation across entire gene families to accelerate understanding of TPD beyond the kinome.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2020.10.038