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 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).
Lippa
Blaise
B
Pfizer, Inc., PGRD Groton, 558 Eastern Point Road, Groton, CT 06340, USA. blaise.lippa@cubist.com
Pan
Gonghua
G
Corbett
Matthew
M
Li
Chao
C
Kauffman
Goss S
GS
Pandit
Jayvardhan
J
Robinson
Shaughnessy
S
Wei
Liuqing
L
Kozina
Ekaterina
E
Marr
Eric S
ES
Borzillo
Gary
G
Knauth
Elisabeth
E
Barbacci-Tobin
Elsa G
EG
Vincent
Patrick
P
Troutman
Merin
M
Baker
Deborah
D
Rajamohan
Francis
F
Kakar
Shefali
S
Clark
Tracey
T
Morris
Joel
J
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
D000970:Antineoplastic Agents; D011743:Pyrimidines; D011758:Pyrroles; D013141:Spiro Compounds; D051057:Proto-Oncogene Proteins c-akt