Novel Allosteric Inhibitor-Derived AKT Proteolysis Targeting Chimeras (PROTACs) Enable Potent and Selective AKT Degradation in KRAS/BRAF Mutant Cells,Journal of Medicinal Chemistry

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Novel Allosteric Inhibitor-Derived AKT Proteolysis Targeting Chimeras (PROTACs) Enable Potent and Selective AKT Degradation in KRAS/BRAF Mutant Cells
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-10-05 , DOI: 10.1021/acs.jmedchem.2c01454
Xufen Yu _{1,

2} , Jia Xu ₂ , Kaitlyn M Cahuzac ₂ , Ling Xie ₃ , Yudao Shen _{1,

2} , Xian Chen ₃ , Jing Liu _{1,

2} , Ramon E Parsons ₂ , Jian Jin _{1,

2}

Affiliation

AKT is an important target for cancer therapeutics. Significant advancements have been made in developing ATP-competitive and allosteric AKT inhibitors. Recently, several AKT proteolysis targeting chimeras (PROTACs) derived from ATP-competitive AKT inhibitors have been reported, including MS21. While MS21 potently degraded AKT and inhibited the growth in tumor cells harboring PI3K/PTEN pathway mutation, it was largely ineffective in degrading AKT in KRAS/BRAF mutated cells as a single agent. To overcome the AKT degradation resistance in KRAS/BRAF mutated cells, we developed novel AKT PROTACs derived from an AKT allosteric inhibitor, including degrader 62 (MS15). 62 displayed potent and selective AKT degradation activity and potent antiproliferative activity in KRAS/BRAF mutated cancer cells, in addition to PI3K/PTEN mutated cancer cells. Furthermore, 62 was bioavailable in mice through intraperitoneal administration. Overall, 62 is a valuable chemical tool to degrade AKT in cells harboring KRAS/BRAF mutation and expands the tool box for pharmacologically modulating AKT.

中文翻译：

新型变构抑制剂衍生的 AKT 蛋白水解靶向嵌合体 (PROTAC) 可在 KRAS/BRAF 突变细胞中实现有效且选择性的 AKT 降解

AKT 是癌症治疗的重要靶点。ATP 竞争性和变构 AKT 抑制剂的开发已取得重大进展。最近，报道了几种源自 ATP 竞争性 AKT 抑制剂的 AKT 蛋白水解靶向嵌合体 (PROTAC)，其中包括 MS21。虽然 MS21 能有效降解 AKT 并抑制携带 PI3K/PTEN 通路突变的肿瘤细胞的生长，但作为单一药物，它在降解 KRAS/BRAF 突变细胞中的 AKT 方面基本上无效。为了克服 KRAS/BRAF 突变细胞中的 AKT 降解抗性，我们开发了源自 AKT 变构抑制剂的新型 AKT PROTAC，包括降解剂62 (MS15)。除了 PI3K/PTEN 突变的癌细胞外， 62在 KRAS/BRAF 突变的癌细胞中也显示出有效和选择性的 AKT 降解活性和有效的抗增殖活性。此外，62通过腹膜内给药在小鼠中具有生物利用度。总体而言，62是一种有价值的化学工具，可降解含有 KRAS/BRAF 突变的细胞中的 AKT，并扩展了药理调节 AKT 的工具箱。

更新日期：2022-10-05

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