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.

中文翻译：

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发现第一个针对假激酶 TRIB2 的选择性和强效 PROTAC 降解剂


假激酶 TRIB2 是 CAMK 丝氨酸/苏氨酸蛋白激酶家族的一员，通过磷酸化非依赖性机制调节各种细胞过程。TRIB2 的失调与促进肿瘤生长、转移和治疗耐药有关，使其成为癌症治疗的有前途的靶点。在这项研究中，我们通过不同长度和组成的接头将 TRIB2 结合剂 1 与 VHL 或 CRBN 配体偶联，设计并合成了一系列 TRIB2 PROTAC 降解剂。在这些化合物中，5k 在前列腺癌 PC3 细胞中表现出有效的 TRIB2 降解，DC50 值为 16.84 nM（95 % CI：13.66–20.64 nM）。机制研究表明，5k 直接与 TRIB2 相互作用，通过 CRBN 依赖性泛素-蛋白酶体途径选择性诱导其降解。此外，5k 在抑制细胞增殖和诱导细胞凋亡方面优于单独的 TRIB2 结合剂，证实 TRIB2 蛋白降解可能是 TRIB2 相关癌症的一种有前途的治疗策略。此外，化合物 5k 也可作为探测 TRIB2 生物学的有效工具。