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 of 2 , a potent series of N- 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. Compound 12 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.