Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting Del19/T790M/C797S Mutation,ACS Medicinal Chemistry Letters

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Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting Del19/T790M/C797S Mutation
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2022-01-14 , DOI: 10.1021/acsmedchemlett.1c00645
Hualin Zhang _{1,

2} , Ruliang Xie ₂ , Hawaa Ai-Furas ₃ , Yupeng Li ₄ , Qingxia Wu ₂ , Jian Li ₁ , Fang Xu ₃ , Tianfeng Xu _{2,

5,

6}

Affiliation

The tertiary epidermal growth factor receptor (EGFR) C797S mutation predominates in the acquired mutational resistance in cancer patients to third-generation EGFR inhibitors. Small-molecule inhibitors targeting the EGFR C797S mutation have been developed with good efficiency. However, these compounds may still induce new EGFR mutations to evade the inhibition pathway. One EGFR protein degrader based on an allosteric inhibitor has shown some benefits of degrading the EGFR L858R/T790M/C797S triple mutant. However, the degrader of the other important triple EGFR mutation Del19/T790M/C797S has not been reported. Here we present the design and synthesis of a series of EGFR proteolysis-targeting chimeras (PROTACs) that can rapidly and potently induce EGFR degradation in Ba/F3 cells expressing the EGFR^{Del19/T790M/C797S} mutant. One representative compound 6h time- and dose-dependently induced EGFR degradation with a DC₅₀ of 8 nM. It also showed good antiproliferation activity (IC₅₀ = 0.02 μM) against Ba/F3-EGFR^{Del19/T790M/C797S} cells. 6h may serve as a lead compound to develop therapeutic agents for the treatment of resistant non-small cell lung cancer patients with EGFR C797S mutants.

中文翻译：

针对 Del19/T790M/C797S 突变的新型 EGFR PROTAC 的设计、合成和生物学评价

三级表皮生长因子受体 (EGFR) C797S 突变在癌症患者对第三代 EGFR 抑制剂的获得性突变耐药中占主导地位。以 EGFR C797S 突变为靶点的小分子抑制剂已经开发出来，效率很高。然而，这些化合物仍可能诱导新的 EGFR 突变以逃避抑制途径。一种基于变构抑制剂的 EGFR 蛋白降解剂显示出降解 EGFR L858R/T790M/C797S 三重突变体的一些好处。然而，另一个重要的三重 EGFR 突变 Del19/T790M/C797S 的降解剂尚未见报道。在这里，我们介绍了一系列 EGFR 蛋白水解靶向嵌合体 (PROTAC) 的设计和合成，这些嵌合体可以快速有效地诱导表达 EGFR ^{Del19/T790M/C797S的 Ba/F3 细胞中的 EGFR 降解}变种人。一种代表性化合物6小时时间和剂量依赖性诱导 EGFR 降解，DC ₅₀为 8 nM。它还对 Ba/F3-EGFR ^{Del19/T790M/C797S}细胞显示出良好的抗增殖活性 (IC ₅₀ = 0.02 μM) 。6h可作为先导化合物开发用于治疗具有 EGFR C797S 突变体的耐药性非小细胞肺癌患者的治疗剂。

更新日期：2022-02-10

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