Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model.
A series of naphthyridine and naphthyridinone allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been optimized to have potent dual activity against the activated kinase as well as the activation of Akt in cells. One molecule in particular, compound 17, has potent inhibitory activity against Akt1 and 2 in vivo in a mouse lung and efficacy in a tumor xenograft model.
Bilodeau
Mark T
MT
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486 USA. mark_bilodeau@merck.com
Balitza
Adrienne E
AE
Hoffman
Jacob M
JM
Manley
Peter J
PJ
Barnett
Stanley F
SF
Defeo-Jones
Deborah
D
Haskell
Kathleen
K
Jones
Raymond E
RE
Leander
Karen
K
Robinson
Ronald G
RG
Smith
Anthony M
AM
Huber
Hans E
HE
Hartman
George D
GD
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D004195:Disease Models, Animal; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009287:Naphthyridines; D051057:Proto-Oncogene Proteins c-akt