3MVJ

Human cyclic AMP-dependent protein kinase PKA inhibitor complex

3MVJ の概要

• エントリーDOI: 10.2210/pdb3mvj/pdb
• 関連するPDBエントリー: 3MV5 3MVH
• 分子名称: 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)
• 機能のキーワード: kinase inhibitor, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm. Isoform 2: Cell projection, cilium, flagellum : P17612
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 136053.52

構造登録者

Pandit, J.,Vajdos, F. (登録日: 2010-05-04, 公開日: 2010-06-02, 最終更新日: 2024-10-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.49 Å)