Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development

Katherine A. Donovan, Fleur M. Ferguson, Jonathan W. Bushman, Nicholas A. Eleuteri, Debabrata Bhunia, Seong Shick Ryu, Li Tan, Kun Shi, Hong Yue, Xiaoxi Liu, Dennis Dobrovolsky, Baishan Jiang, Jinhua Wang, Mingfeng Hao, Inchul You, Mingxing Teng, Yanke Liang, John Hatcher, Zhengnian Li, Theresa D. ManzBrian Groendyke, Wanyi Hu, Yunju Nam, Sandip Sengupta, Hanna Cho, Injae Shin, Michael P. Agius, Irene M. Ghobrial, Michelle W. Ma, Jianwei Che, Sara J. Buhrlage, Taebo Sim, Nathanael S. Gray, Eric S. Fischer

Research output: Contribution to journalArticlepeer-review

140 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1714-1731.e10
JournalCell
Volume183
Issue number6
DOIs
Publication statusPublished - 2020 Dec 10

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Inc.

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology

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