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Discovery of the first selective and potent PROTAC degrader for the pseudokinase TRIB2
Chaowei Wen1, Prathibha R Gajjala2, Yihan Liu3
1International 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.
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.
Insights
We developed novel TRIB2 PROTAC degraders for cancer therapy. Compound 5k effectively degrades TRIB2 protein, inhibiting cancer cell growth and offering a new therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Pseudokinase TRIB2 regulates cellular processes via phosphorylation-independent mechanisms.
- TRIB2 dysregulation is linked to tumor growth, metastasis, and therapy resistance in cancers.
Purpose of the Study:
- To design and synthesize TRIB2 PROTAC degraders for cancer treatment.
- To evaluate the efficacy of TRIB2 degradation as a therapeutic strategy.
Main Methods:
- Conjugation of a TRIB2 binder with VHL or CRBN ligands to create PROTAC degraders.
- Assessment of TRIB2 degradation using DC50 values in prostate cancer PC3 cells.
- Mechanistic studies on TRIB2 interaction and degradation pathway.
Main Results:
- Compound 5k showed potent TRIB2 degradation (DC50 = 16.84 nM) in PC3 cells.
- 5k induced TRIB2 degradation via a CRBN-dependent ubiquitin-proteasomal pathway.
- 5k inhibited cell proliferation and induced apoptosis more effectively than the TRIB2 binder alone.
Conclusions:
- TRIB2 protein degradation is a viable therapeutic strategy for TRIB2-associated cancers.
- Compound 5k is a potent TRIB2 degrader and a valuable tool for studying TRIB2 biology.
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