Author/Authors :
Blaise Lippa، نويسنده , , Gonghua Pan، نويسنده , , Matthew Corbett، نويسنده , , Chao Li، نويسنده , , Goss S. Kauffman، نويسنده , , Jayvardhan Pandit، نويسنده , , Shaughnessy Robinson، نويسنده , , Liuqing Wei، نويسنده , , Ekaterina Kozina، نويسنده , , Eric S. Marr، نويسنده , , Gary Borzillo، نويسنده , , Elisabeth Knauth، نويسنده , , Elsa G. Barbacci-Tobin، نويسنده , , Patrick Vincent، نويسنده , , Merin Troutman، نويسنده , , Deborah Baker، نويسنده , , Francis Rajamohan، نويسنده , , Shefali Kakar، نويسنده , , Tracey Clark، نويسنده , , Joel Morris، نويسنده ,
Abstract :
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).
Keywords :
Akt , Pyrrolopyrimidine , Imidazopiperidine , Spiroindoline
