3MVJ

Human cyclic AMP-dependent protein kinase PKA inhibitor complex

Summary for 3MVJ

• Entry DOI: 10.2210/pdb3mvj/pdb
• Related: 3MV5 3MVH
• Descriptor: cAMP-dependent protein kinase catalytic subunit alpha, cAMP-dependent protein kinase inhibitor alpha, (3R)-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine, ... (4 entities in total)
• Functional Keywords: kinase inhibitor, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm. Isoform 2: Cell projection, cilium, flagellum : P17612
• Total number of polymer chains: 6
• Total formula weight: 136053.52

Authors

Pandit, J.,Vajdos, F. (deposition date: 2010-05-04, release date: 2010-06-02, Last modification date: 2024-10-30)

Primary citation

Freeman-Cook, K.D.,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, M.J.,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., 53:4615-4622, 2010

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.

PubMed: 20481595
DOI: 10.1021/jm1003842

Experimental method

X-RAY DIFFRACTION (2.49 Å)