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Eur J Med Chem. 2017 Sep 29;138:543-551. doi: 10.1016/j.ejmech.2017.06.067. Epub 2017 Jun 30.

Structural optimization elaborates novel potent Akt inhibitors with promising anticancer activity.

Author information

1
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China.
2
The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3
The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: miwang@mdanderson.org.
4
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China. Electronic address: guisenzhao@sdu.edu.cn.

Abstract

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 G2/M phase, and significantly downregulated the phosphorylation of Akt downstream effectors GSK3β and S6 in Jeko-1 cells.

KEYWORDS:

Akt; Anticancer; Docking; Mantle cell lymphoma; Piperidyl; Pyrrolopyrimidines

PMID:
28704757
DOI:
10.1016/j.ejmech.2017.06.067
[Indexed for MEDLINE]

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