Design of selective, ATP-competitive inhibitors of Akt.

Article Details

Citation

Freeman-Cook KD, Autry C, Borzillo G, Gordon D, Barbacci-Tobin E, Bernardo V, Briere D, Clark T, Corbett M, Jakubczak J, Kakar S, Knauth E, Lippa B, Luzzio MJ, Mansour M, Martinelli G, Marx M, Nelson K, Pandit J, Rajamohan F, Robinson S, Subramanyam C, Wei L, Wythes M, Morris J

Design of selective, ATP-competitive inhibitors of Akt.

J Med Chem. 2010 Jun 24;53(12):4615-22. doi: 10.1021/jm1003842.

PubMed ID
20481595 [ View in PubMed
]
Abstract

This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
RAC-alpha serine/threonine-protein kinaseP31749Details
cAMP-dependent protein kinase catalytic subunit alphaP17612Details