Synthesis and structure based optimization of novel Akt inhibitors

Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC50 of 2.4 ± 0.6 nM, Akt cell potency of 50 ± 19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po).

Graphical abstractAkt1 X-ray co-crystal structures are utilized to optimize the potency of an HTS hit to a spiroindoline pyrrolopyrimidine. The synthesis and SAR of multiple inhibitor classes, along with the efficacy of one lead compound in a tumor model are presented.Figure optionsDownload full-size imageDownload as PowerPoint slide