Structure-based optimization of aminothiadiazole inhibitors of AKT

We report here the discovery and structure-guided optimization of a novel series of AKT kinase inhibitors. Based on docking studies for the predicted active bound-conformation of2, a potent series ofN-substituted-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amines was developed. Compounds in the series achieve AKT pathway inhibition in cancer cells, as measured by inhibition of pathway proteins pGSK and pFKHR. Compound12 was further evaluated in a single dose PK/PD in vivo study in tumor-bearing mice and demonstrated inhibition of phosphorylation of the direct substrate GSK and pathway biomarker S6.
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research