By merging the critical pharmacophore of EGFR/HER2 and HDAC inhibitors into one compound, a novel series of EGFR, HER-2, and HDAC multitarget inhibitors were synthesized. Compounds 9a–l contained 4-anilinoquinazolines with C-6 triazole-linked long alkyl chains of hydroxamic acid and displayed excellent inhibition against these enzymes (compound 9d exhibited the best inhibitory potency on wild-type EGFR, HDAC1, and HDAC6 with IC₅₀ values 0.12nM, 0.72nM and 3.2nM individually). Furthermore, compounds 9b and 9d potently inhibited proliferation of five human cancer cell lines (with IC₅₀ values between 0.49 and 8.76μM). Further mechanistic study revealed that compound 9d also regulated the phosphorylation of EGFR and HER2 and histone H3 hyperacetylation on the cellular level and induced remarkable apoptosis in BT-474 cells. Therefore, our study suggested that a system network-based multi-target drug design strategy might provided an alternate drug design method, by taking into account the synergy effect of EGFR, HER-2 and HDAC.

中文翻译：

---

具有异羟肟酸部分的新型6-（1,2,3-三唑-4-基）-4-氨基喹唑啉衍生物的合成与研究

通过将EGFR / HER2和HDAC抑制剂的关键药效​​团合并为一个化合物，合成了一系列新的EGFR，HER-2和HDAC多靶点抑制剂。化合物9a–l包含4-苯胺基喹唑啉和C-6三唑连接的异羟肟酸长烷基链，对这些酶表现出优异的抑制作用（化合物9d对野生型EGFR，HDAC1和HDAC6表现出最佳的抑制作用，IC ₅₀值分别为0.12nM，0.72nM和3.2nM）。此外，化合物9b和9d有效抑制5种人类癌细胞系的增殖（IC _50为值介于0.49和8.76μM之间）。进一步的机理研究表明，化合物9d在细胞水平上还调节EGFR和HER2的磷酸化以及组蛋白H3的超乙酰化，并诱导BT-474细胞显着的凋亡。因此，我们的研究表明，考虑到EGFR，HER-2和HDAC的协同作用，基于系统网络的多目标药物设计策略可能会提供一种替代药物设计方法。