Ding Chao, Chen Shaopeng, Zhang Cunlong, Hu Guangnan, Zhang Wei, Li Lulu, Chen Yu Zong, Tan Chunyan, Jiang Yuyang
Department of Chemistry, Tsinghua University, Beijing 100084, PR China; The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
Bioorg Med Chem. 2017 Jan 1;25(1):27-37. doi: 10.1016/j.bmc.2016.10.006. Epub 2016 Oct 10.
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 IC values 0.12nM, 0.72nM and 3.2nM individually). Furthermore, compounds 9b and 9d potently inhibited proliferation of five human cancer cell lines (with IC 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.
通过将表皮生长因子受体/人表皮生长因子受体2（EGFR/HER2）和组蛋白去乙酰化酶（HDAC）抑制剂的关键药效基团合并到一个化合物中，合成了一系列新型的EGFR、HER-2和HDAC多靶点抑制剂。化合物9a-l含有4-苯胺基喹唑啉，其C-6位通过三唑连接有长链烷基的异羟肟酸，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表现出最佳抑制效力，其IC值分别为0.12nM、0.72nM和3.2nM）。此外，化合物9b和9d有效抑制了五种人类癌细胞系的增殖（IC值在0.49至8.76μM之间）。进一步的机制研究表明，化合物9d在细胞水平上还调节了EGFR和HER2的磷酸化以及组蛋白H3的高乙酰化，并在BT-474细胞中诱导了显著的凋亡。因此，我们的研究表明，基于系统网络的多靶点药物设计策略可能提供一种替代的药物设计方法，通过考虑EGFR、HER-2和HDAC的协同效应。
