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

Autor:	Huang HT; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Dobrovolsky D; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Paulk J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Yang G; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Weisberg EL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Doctor ZM; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Buckley DL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Cho JH; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea., Ko E; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea., Jang J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Shi K; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China., Choi HG; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea., Griffin JD; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA., Li Y; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China., Treon SP; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA., Fischer ES; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Bradner JE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA., Tan L; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China. Electronic address: tanli@sioc.ac.cn., Gray NS; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: nathanael_gray@dfci.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2018 Jan 18; Vol. 25 (1), pp. 88-99.e6. Date of Electronic Publication: 2017 Nov 09.
DOI:	10.1016/j.chembiol.2017.10.005
Abstrakt:	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. (Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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