Structural optimization elaborates novel potent Akt inhibitors with promising anticancer activity

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.