2. Academic Validation
  3. Discovery of the first selective and potent PROTAC degrader for the pseudokinase TRIB2

Discovery of the first selective and potent PROTAC degrader for the pseudokinase TRIB2

  • Eur J Med Chem. 2024 Nov 1:281:117016. doi: 10.1016/j.ejmech.2024.117016.
Chaowei Wen 1,  Prathibha R Gajjala 2,  Yihan Liu 3,  Bingzhong Chen 1,  Mehtab S Bal 4,  Payal Sutaria 4,  Qiao Yuanyuan 2,  Yang Zheng 2,  Yang Zhou 1,  Jinwei Zhang 5,  Weixue Huang 5,  Xiaomei Ren 5,  Zhen Wang 5,  Ke Ding 6,  Arul M Chinnaiyan 7,  Fengtao Zhou 8
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
  • 2 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, United States; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, United States.
  • 3 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, United States; Cancer Biology Program, University of Michigan, Ann Arbor, MI, 48109, United States.
  • 4 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, United States.
  • 5 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
  • 6 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address: dingk@sioc.ac.cn.
  • 7 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, United States; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, United States; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, United States; Department of Urology, University of Michigan, Ann Arbor, MI, 48109, United States; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, 48109, United States. Electronic address: arul@med.umich.edu.
  • 8 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: fengtaozhou@jnu.edu.cn.
PMID: 39520729 DOI: 10.1016/j.ejmech.2024.117016
Abstract

Pseudokinase TRIB2, a member of the CaMK Ser/Thr protein kinase family, regulates various cellular processes through phosphorylation-independent mechanisms. Dysregulation of TRIB2 has been implicated in promoting tumor growth, metastasis, and therapy resistance, making it a promising target for Cancer treatment. In this study, we designed and synthesized a series of TRIB2 PROTAC degraders by conjugating a TRIB2 binder 1 with VHL or CRBN ligands via linkers of varying lengths and compositions. Among these compounds, 5k demonstrated potent TRIB2 degradation with a DC50 value of 16.84 nM (95 % CI: 13.66-20.64 nM) in prostate Cancer PC3 cells. Mechanistic studies revealed that 5k directly interacted with TRIB2, selectively inducing its degradation through a CRBN-dependent ubiquitin-proteasomal pathway. Moreover, 5k outperformed the TRIB2 binder alone in inhibiting cell proliferation and inducing Apoptosis, confirming that TRIB2 protein degradation could be a promising therapeutic strategy for TRIB2-associated cancers. Additionally, compound 5k also serves as an effective tool for probing TRIB2 biology.

Keywords

Apoptosis; PROTACs; Proliferation; Protein degradation; Pseudokinase; TRIB2.

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