2. Academic Validation
  3. A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader

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

  • Cell Chem Biol. 2018 Jan 18;25(1):88-99.e6. doi: 10.1016/j.chembiol.2017.10.005.
Hai-Tsang Huang 1,  Dennis Dobrovolsky 1,  Joshiawa Paulk 2,  Guang Yang 3,  Ellen L Weisberg 2,  Zainab M Doctor 1,  Dennis L Buckley 2,  Joong-Heui Cho 4,  Eunhwa Ko 4,  Jaebong Jang 1,  Kun Shi 5,  Hwan Geun Choi 4,  James D Griffin 6,  Ying Li 7,  Steven P Treon 8,  Eric S Fischer 1,  James E Bradner 6,  Li Tan 9,  Nathanael S Gray 10
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 3 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.
  • 4 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea.
  • 5 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.
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 7 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
  • 8 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.
  • 9 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: [email protected].
  • 10 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: [email protected].
PMID: 29129717 DOI: 10.1016/j.chembiol.2017.10.005
Abstract

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.

Keywords

BTK; FLT3; chemoproteomics; drug design; kinase; protein degradation.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-130665
    99.63%, PROTAC Kinase Degrader