4EJN

Crystal structure of autoinhibited form of AKT1 in complex with N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-3-fluorobenzamide

Summary for 4EJN

• Entry DOI: 10.2210/pdb4ejn/pdb
• Descriptor: RAC-alpha serine/threonine-protein kinase, N-(4-{5-[3-(acetylamino)phenyl]-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl}benzyl)-3-fluorobenzamide, 2-BUTANOL, ... (5 entities in total)
• Functional Keywords: akt1, autoinhibition, allosteric inhibitor, kinase inhibitor, hydrophobic collapase, kinase, atpase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P31749
• Total number of polymer chains: 1
• Total formula weight: 52453.83

Authors

Eathiraj, S. (deposition date: 2012-04-06, release date: 2012-05-23, Last modification date: 2024-10-16)

Primary citation

Ashwell, M.A.,Lapierre, J.M.,Brassard, C.,Bresciano, K.,Bull, C.,Cornell-Kennon, S.,Eathiraj, S.,France, D.S.,Hall, T.,Hill, J.,Kelleher, E.,Khanapurkar, S.,Kizer, D.,Koerner, S.,Link, J.,Liu, Y.,Makhija, S.,Moussa, M.,Namdev, N.,Nguyen, K.,Nicewonger, R.,Palma, R.,Szwaya, J.,Tandon, M.,Uppalapati, U.,Vensel, D.,Volak, L.P.,Volckova, E.,Westlund, N.,Wu, H.,Yang, R.Y.,Chan, T.C.
Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: orally bioavailable, selective, and potent ATP-independent Akt inhibitors.
J.Med.Chem., 55:5291-5310, 2012

PubMed Abstract: This paper describes the implementation of a biochemical and biophysical screening strategy to identify and optimize small molecule Akt1 inhibitors that act through a mechanism distinct from that observed for kinase domain ATP-competitive inhibitors. With the aid of an unphosphorylated Akt1 cocrystal structure of 12j solved at 2.25 Å, it was possible to confirm that as a consequence of binding these novel inhibitors, the ATP binding cleft contained a number of hydrophobic residues that occlude ATP binding as expected. These Akt inhibitors potently inhibit intracellular Akt activation and its downstream target (PRAS40) in vitro. In vivo pharmacodynamic and pharmacokinetic studies with two examples, 12e and 12j, showed the series to be similarly effective at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice.

PubMed: 22533986
DOI: 10.1021/jm300276x

Experimental method

X-RAY DIFFRACTION (2.19 Å)