2. Academic Validation
  3. Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development

Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development

  • Cell. 2020 Dec 10;183(6):1714-1731.e10. doi: 10.1016/j.cell.2020.10.038.
Katherine A Donovan 1,  Fleur M Ferguson 1,  Jonathan W Bushman 1,  Nicholas A Eleuteri 2,  Debabrata Bhunia 3,  SeongShick Ryu 4,  Li Tan 5,  Kun Shi 6,  Hong Yue 1,  Xiaoxi Liu 1,  Dennis Dobrovolsky 1,  Baishan Jiang 1,  Jinhua Wang 1,  Mingfeng Hao 1,  Inchul You 1,  Mingxing Teng 1,  Yanke Liang 1,  John Hatcher 1,  Zhengnian Li 1,  Theresa D Manz 7,  Brian Groendyke 1,  Wanyi Hu 2,  Yunju Nam 8,  Sandip Sengupta 9,  Hanna Cho 8,  Injae Shin 4,  Michael P Agius 10,  Irene M Ghobrial 10,  Michelle W Ma 1,  Jianwei Che 1,  Sara J Buhrlage 1,  Taebo Sim 11,  Nathanael S Gray 12,  Eric S Fischer 13
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3 Chemical Kinomics Research Center, Korea Institute of Science and Technology, 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
  • 4 KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, 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; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 6 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.
  • 7 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbruecken, Germany.
  • 8 KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
  • 9 Chemical Kinomics Research Center, Korea Institute of Science and Technology, 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
  • 10 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 11 Chemical Kinomics Research Center, Korea Institute of Science and Technology, 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address: tbsim@yuhs.ac.
  • 12 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: nathanael_gray@dfci.harvard.edu.
  • 13 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: eric_fischer@dfci.harvard.edu.
PMID: 33275901 DOI: 10.1016/j.cell.2020.10.038
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.

Keywords

E3 ligase; IMiD; PROTAC; degrader; kinase; targeted degradation; ubiquitin; ubiquitin proteasome system.

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