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.

Automated summary

We have discovered and optimized a novel series of AKT kinase inhibitors, guided by the structure of the target protein. Docking studies led to the development of a potent series of N-substituted-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amines. These compounds inhibit the AKT pathway in cancer cells by suppressing the phosphorylation of pathway proteins pGSK and pFKHR. In vivo studies using compound 12 showed inhibition of phosphorylation of the direct substrate GSK and pathway biomarker S6 in tumor-bearing mice.