Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model

Mark T Bilodeau; Adrienne E Balitza; Jacob M Hoffman; Peter J Manley; Stanley F Barnett; Deborah Defeo-Jones; Kathleen Haskell; Raymond E Jones; Karen Leander; Ronald G Robinson; Anthony M Smith; Hans E Huber; George D Hartman

doi:10.1016/j.bmcl.2008.04.074

Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model

Bioorg Med Chem Lett. 2008 Jun 1;18(11):3178-82. doi: 10.1016/j.bmcl.2008.04.074. Epub 2008 May 1.

Authors

Mark T Bilodeau¹, Adrienne E Balitza, Jacob M Hoffman, Peter J Manley, Stanley F Barnett, Deborah Defeo-Jones, Kathleen Haskell, Raymond E Jones, Karen Leander, Ronald G Robinson, Anthony M Smith, Hans E Huber, George D Hartman

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486 USA. [email protected]

PMID: 18479914
DOI: 10.1016/j.bmcl.2008.04.074

Abstract

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Combinatorial Chemistry Techniques
Disease Models, Animal
Drug Design
Drug Screening Assays, Antitumor
Humans
Mice
Naphthyridines / chemical synthesis*
Naphthyridines / chemistry
Naphthyridines / pharmacology*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Naphthyridines
Proto-Oncogene Proteins c-akt