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 (Tmax = 0.5 h) and 41 % bioavailability. These findings highlight JL16 and JL18 as promising AKT inhibitors for further preclinical development.