Abstract

A new class of EGFR PROTACs based on pomalidomide was developed, synthesised, and tested for their cytotoxic activity against a panel of human cancer cells. Compounds 15–21 were showed to be more effective against the four tested cell lines than erlotinib. In particular, compound 16 was found to be the most potent counterpart as it was 5.55, 4.34, 5.04, and 7.18 times more active than erlotinib against MCF-7, HepG-2, HCT-116, and A549 cells, respectively. Compound 15 was revealed to be more active than doxorubicin against the four tested cell lines. Furthermore, the most potent cytotoxic compounds were studied further for their kinase inhibitory effects against EGFR^WT and EGFR^T790M using HTRF test. Compound 16 showed to be the most effective against both kinds of EGFR, with IC₅₀ values of 0.10 and 4.02 µM, respectively. Compound 16 could effectively degrade EGFR protein through ubiquitination (D_max = 96%) at 72 h in the tested cells.

摘要

开发、合成了一类基于泊马度胺的新型 EGFR PROTAC，并测试了它们对一组人类癌细胞的细胞毒活性。化合物15 – 21被证明比厄洛替尼对四种测试细胞系更有效。特别是，化合物16被发现是最有效的对应物，因为它对 MCF-7、HepG-2、HCT-116 和 A549 细胞的活性分别是厄洛替尼的 5.55、4.34、5.04 和 7.18 倍。化合物15对四种测试细胞系的活性比多柔比星更强。^{此外，进一步研究了最有效的细胞毒性化合物对 EGFR WT}和 EGFR ^T790M的激酶抑制作用使用 HTRF 测试。化合物16显示对两种 EGFR 最有效，IC ₅₀值分别为 0.10 和 4.02 µM。化合物16可以在被测细胞中72小时通过泛素化(D _{max = 96%)有效降解EGFR蛋白。}