The mammalian target of rapamycin (mTOR) has been proved to be an effective target for cancer therapy. Two kinds of mTOR inhibitors, the rapalogs and mTOR kinase inhibitors (TORKi), have been developed and clinically validated in several types of malignancies. Compared with rapalogs, TORKi can exert better antitumor activity by inhibiting both mTORC1 and mTORC2, but the clinical development of current TORKi candidates has been relative slow, more TORKi with novel scaffold need to be developed to expand the current pipelines. In this study, a series of 9-methyl-9H-purine and thieno[3, 2-d]pyrimidine derivatives were designed, synthesized and biological evaluation. Most of these compounds exhibited good mTOR kinase inhibitory activity and selectivity over PI3Kα. Subsequent antiproliferative assay allowed us to identify the lead compound 15i, which display nanomolar to low micromolar IC₅₀s against six human cancer cell lines. 15i could induce cell cycle arrest of MCF-7, PC-3 and A549 cells at the G0/G1 phase and suppress the migration and invasion of these cancer cells by suppressing the phosphorylation of AKT and P70S6 kinase. It could also regulate autophagy-related proteins to induce autophagy. Therefore, 15i would be a starting point for the development of new TORKi as anticancer drug.

哺乳动物雷帕霉素靶标 (mTOR) 已被证明是癌症治疗的有效靶标。已经开发了两种 mTOR 抑制剂，rapalogs 和 mTOR 激酶抑制剂 (TORKi)，并在多种类型的恶性肿瘤中进行了临床验证。与 rapalogs 相比，TORKi 可以通过同时抑制 mTORC1 和 mTORC2 发挥更好的抗肿瘤活性，但目前 TORKi 候选药物的临床开发相对缓慢，需要开发更多具有新型支架的 TORKi 以扩展目前的管线。在本研究中，一系列 9-methyl-9 H -purine 和 thieno[3, 2- d]嘧啶衍生物的设计、合成和生物学评价。大多数这些化合物表现出良好的 mTOR 激酶抑制活性和对 PI3Kα 的选择性。随后的抗增殖试验使我们能够鉴定先导化合物15i ，它显示出对六种人类癌细胞系的纳摩尔至低微摩尔 IC _{50 s。}15i可诱导MCF-7、PC-3和A549细胞周期停滞在G0/G1期，通过抑制AKT和P70S6激酶的磷酸化来抑制这些癌细胞的迁移和侵袭。它还可以调节自噬相关蛋白以诱导自噬。因此，15i将是开发新型 TORKi 作为抗癌药物的起点。