Blaise Lippa,
Gonghua Pan,
Matthew Corbett,
Chao Li,
Goss S Kauffman,
Jayvardhan Pandit,
Shaughnessy Robinson,
Liuqing Wei,
Ekaterina Kozina,
Eric S Marr,
Gary Borzillo,
Elisabeth Knauth,
Elsa G Barbacci-Tobin, Patrick Vincent,
Merin Troutman,
Deborah Baker,
Francis Rajamohan,
Shefali Kakar,
Tracey Clark,
Joel Morris
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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 IC(50) 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).
Bioorganic & medicinal chemistry letters 07/2008; 18(11):3359-63. · 2.65 Impact Factor
