The discovery of novel N-heterocyclic-based AKT inhibitors with potential efficacy against prostate cancer

Akt, a serine/threonine protein kinase that plays a pivotal role in the PI3K/Akt/mTOR pathway, is overexpressed or hyperactivated in various cancers, including prostate, breast, and lung cancers. A series of novel nitrogen-containing aromatic heterocyclic compounds were designed, synthesized, and evaluated for Akt inhibition and Anticancer activities. Among these, JL16 and JL18 emerged as potent inhibitors of Akt1 kinase, with IC₅₀ values of 7.1 ± 1.2 nM and 8.8 ± 1.3 nM, respectively. Both compounds also demonstrated significant antiproliferative effects against PC-3 prostate Cancer cells, with IC₅₀ values of 2.9 ± 0.7 μM (JL16) and 3.0 ± 0.6 μM (JL18). Mechanistic studies revealed that JL16 and JL18 reduced phosphorylated GSK3β levels, confirming Akt target engagement in cells. Notably, JL18 exhibited favorable pharmacokinetic properties in mice, including rapid oral absorption (T_max = 0.5 h) and 41 % bioavailability. These findings highlight JL16 and JL18 as promising Akt inhibitors for further preclinical development.

AKT inhibitors; Anticancer; GSK3β; Molecular docking; Prostate cancer.