Liu Yang, Yin Yanzhen, Zhang Zhen, Li Carrie J, Zhang Hui, Zhang Daoguang, Jiang Changying, Nomie Krystle, Zhang Liang, Wang Michael L, Zhao Guisen
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China.
The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Eur J Med Chem. 2017 Sep 29;138:543-551. doi: 10.1016/j.ejmech.2017.06.067. Epub 2017 Jun 30.
Targeting of Akt has been validated as a well rationalized approach to cancer treatment, and represents a promising therapeutic strategy for aggressive hematologic malignancies. We describe herein an exploration of novel Akt inhibitors for cancer therapy through structural optimization of previously described 4-(piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives. Our studies yielded a novel series of pyrrolopyrimidine based phenylpiperidine carboxamides capable of potent inhibition of Akt1. Notably, 10h exhibited robust antiproliferative effects in both mantle cell lymphoma cell lines and primary patient tumor cells. Low micromolar doses of 10h induced cell apoptosis and cell cycle arrest in G/M phase, and significantly downregulated the phosphorylation of Akt downstream effectors GSK3β and S6 in Jeko-1 cells.
靶向Akt已被确认为一种合理的癌症治疗方法，是侵袭性血液系统恶性肿瘤颇具前景的治疗策略。我们在此描述了通过对先前报道的4-(哌嗪-1-基)-7H-吡咯并[2,3-d]嘧啶衍生物进行结构优化来探索新型Akt抑制剂用于癌症治疗的过程。我们的研究产生了一系列基于吡咯并嘧啶的苯基哌啶羧酰胺，它们能够有效抑制Akt1。值得注意的是，10h在套细胞淋巴瘤细胞系和原发性患者肿瘤细胞中均表现出强大的抗增殖作用。低微摩尔剂量的10h诱导细胞凋亡并使细胞周期停滞在G/M期，并显著下调Jeko-1细胞中Akt下游效应物GSK3β和S6的磷酸化水平。
