Design, synthesis and biological evaluation of AKT inhibitors bearing a piperidin-4-yl appendant

MedChemComm
Daoguang ZhangGuisen Zhao

Abstract

A series of AKT inhibitors possessing a piperidin-4-yl side chain was designed and synthesized. Some of them showed high AKT1 inhibitory activity and potent anti-proliferative effect on PC-3 prostate cancer cells in the preliminary screening. Further studies revealed the most potent compound, 10h, as a pan-AKT inhibitor. Compound 10h was able to inhibit the cellular phosphorylation of AKT effectively and induce apoptosis of PC-3 cells. It also showed high metabolic stability in human liver microsomes. Preclinical characterization of 10h, a promising lead AKT inhibitor, as a potential anti-prostate cancer therapeutic needs to be further investigated.

References

Nov 17, 2005·Oncogene·Deborah A Altomare, Joseph R Testa
Apr 25, 2007·Journal of Medicinal Chemistry·Gordon SaxtyRobin A Carr
Apr 25, 2007·Journal of Medicinal Chemistry·Alastair DonaldIan Collins
Apr 22, 2017·Cell·Brendan D Manning, Alex Toker
May 17, 2017·Bioorganic & Medicinal Chemistry Letters·Bayard R Huck, Igor Mochalkin

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Methods Mentioned

BETA
column chromatography
homogeneous time-resolved fluorescence
protein assay
flow cytometry

Clinical Trials Mentioned

NCT01692262
NCT02525068

Software Mentioned

Flowjo
GraphPad Prism

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