title: Synthesis and structure based optimization of novel Akt inhibitors.
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).
authors.affiliation: Pfizer, Inc., PGRD Groton, 558 Eastern Point Road, Groton, CT 06340, USA. blaise.lippa@cubist.com
authors.forename: Blaise
authors.initials: B
authors.lastname: Lippa
authors.forename: Gonghua
authors.initials: G
authors.lastname: Pan
authors.forename: Matthew
authors.initials: M
authors.lastname: Corbett
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.forename: Goss S
authors.initials: GS
authors.lastname: Kauffman
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.forename: Shaughnessy
authors.initials: S
authors.lastname: Robinson
authors.forename: Liuqing
authors.initials: L
authors.lastname: Wei
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Kozina
authors.forename: Eric S
authors.initials: ES
authors.lastname: Marr
authors.forename: Gary
authors.initials: G
authors.lastname: Borzillo
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Knauth
authors.forename: Elsa G
authors.initials: EG
authors.lastname: Barbacci-Tobin
authors.forename: Patrick
authors.initials: P
authors.lastname: Vincent
authors.forename: Merin
authors.initials: M
authors.lastname: Troutman
authors.forename: Deborah
authors.initials: D
authors.lastname: Baker
authors.forename: Francis
authors.initials: F
authors.lastname: Rajamohan
authors.forename: Shefali
authors.initials: S
authors.lastname: Kakar
authors.forename: Tracey
authors.initials: T
authors.lastname: Clark
authors.forename: Joel
authors.initials: J
authors.lastname: Morris
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D015195:Drug Design; D020128:Inhibitory Concentration 50; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D011758:Pyrroles; D013141:Spiro Compounds; D051057:Proto-Oncogene Proteins c-akt