Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC,Journal of Medicinal Chemistry

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Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-29 , DOI: 10.1021/acs.jmedchem.4c00577
Kamila Karpińska ₁ , Dawid Mehlich _{1,

2} , Venkata R Sabbasani ₃ , Michał Łomiak ₁ , Pedro Torres-Ayuso ₄ , Katarzyna Wróbel ₁ , Vi Nguyen-Phuong Truong ₁ , Remigiusz Serwa ₅ , Rolf E Swenson ₃ , John Brognard ₂ , Anna A Marusiak ₁

Affiliation

Triple-negative breast cancer (TNBC) is associated with poor prognosis because of the lack of effective therapies. Mixed-lineage protein kinase 3 (MLK3) is a protein that is often upregulated in TNBC and involved in driving the tumorigenic potential of cancer cells. Here, we present a selective MLK3 degrader, CEP1347-VHL-02, based on the pan-MLK inhibitor CEP1347 and a ligand for E3 ligase von Hippel–Lindau (VHL) by employing proteolysis-targeting chimera (PROTAC) technology. Our compound effectively targeted MLK3 for degradation via the ubiquitin-proteasome system in several cell line models but did not degrade other MLK family members. Furthermore, we showed that CEP1347-VHL-02 robustly degraded MLK3 and inhibited its oncogenic activity in TNBC, measured as a reduction of clonogenic and migratory potential, cell cycle arrest, and the induction of apoptosis in MDA-MB-468 cells. In conclusion, we present CEP1347-VHL-02 as a novel MLK3 degrader that may be a promising new strategy to target MLK3 in TNBC.

中文翻译：

新型 CEP1347-VHL-02 PROTAC 化合物选择性降解 MLK3 限制了 TNBC 的致癌潜力

由于缺乏有效的治疗方法，三阴性乳腺癌（TNBC）与预后不良相关。混合谱系蛋白激酶 3 (MLK3) 是一种在 TNBC 中经常上调的蛋白质，并参与驱动癌细胞的致瘤潜力。在这里，我们通过采用蛋白水解靶向嵌合体 (PROTAC) 技术，基于泛 MLK 抑制剂 CEP1347 和 E3 连接酶 von Hippel-Lindau (VHL) 配体，提出了一种选择性 MLK3 降解剂 CEP1347-VHL-02。我们的化合物在多种细胞系模型中有效地靶向 MLK3，通过泛素蛋白酶体系统进行降解，但不会降解其他 MLK 家族成员。此外，我们还发现，CEP1347-VHL-02 可强力降解 MLK3 并抑制其在 TNBC 中的致癌活性，测量结果为 MDA-MB-468 细胞中克隆形成和迁移潜力的减少、细胞周期停滞以及细胞凋亡的诱导。总之，我们提出 CEP1347-VHL-02 作为一种新型 MLK3 降解剂，可能是 TNBC 中针对 MLK3 的一种有前途的新策略。

更新日期：2024-08-29

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