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

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-

SUBMITTER: Wen C 

PROVIDER: S-EPMC12135709 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature