Li Wenlu, Sun Qinsheng, Song Lu, Gao Chunmei, Liu Feng, Chen Yuzong, Jiang Yuyang
Department of Chemistry, Tsinghua University, Beijing 100084, PR China; The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, PR China.
Eur J Med Chem. 2017 Dec 1;141:721-733. doi: 10.1016/j.ejmech.2017.09.002. Epub 2017 Oct 6.
PI3K/Akt/mTOR and hedgehog (Hh) signalings are two important pathways in breast cancer, which are usually connected with the drug resistance and cancer migration. Many studies indicated that PI3K/Akt/mTOR inhibitors and Hh inhibitors displayed synergistic effects, and the combination of the two signaling drugs could delay drug resistance and inhibit cancer migration in breast cancer. Therefore, the development of molecules simultaneously inhibiting these two pathways is urgent needed. Based on the structures of PI3K inhibitor buparlisib and Hh inhibitor vismodegib, a series of hybrid structures were designed and synthesized utilizing rational drug design and computer-based drug design. Several compounds displayed excellent antiproliferative activities against several breast cancer cell lines, including triple-negative breast cancer (TNBC) MDA-MB-231 cell. Further mechanistic studies demonstrated that the representative compound 9i could inhibit both PI3K/Akt/mTOR and hedgehog (Hh) signalings by inhibiting the phosphorylation of S6K and Akt as well as decreasing the SAG elevated expression of Gli1. Compound 9i could also induce apoptosis remarkably in T47D and MDA-MB-231 cells. In the transwell assay, 9i showed significant inhibition on the migration of MDA-MB-231.
PI3K/Akt/mTOR和刺猬信号通路（Hh）是乳腺癌中的两条重要信号通路，它们通常与耐药性和癌症迁移相关。许多研究表明，PI3K/Akt/mTOR抑制剂和Hh抑制剂具有协同作用，两种信号通路药物联合使用可延缓乳腺癌的耐药性并抑制癌症迁移。因此，迫切需要开发同时抑制这两条信号通路的分子。基于PI3K抑制剂布帕利昔和Hh抑制剂维莫德吉的结构，利用合理药物设计和计算机辅助药物设计设计并合成了一系列杂合结构。几种化合物对多种乳腺癌细胞系，包括三阴性乳腺癌（TNBC）MDA-MB-231细胞，显示出优异的抗增殖活性。进一步的机制研究表明，代表性化合物9i可通过抑制S6K和Akt的磷酸化以及降低Gli1的SAG升高表达来抑制PI3K/Akt/mTOR和刺猬信号通路（Hh）。化合物9i还可在T47D和MDA-MB-231细胞中显著诱导凋亡。在Transwell实验中，9i对MDA-MB-231细胞的迁移显示出显著抑制作用。
