3QCX

Phosphoinositide-Dependent Kinase-1 (PDK1) kinase domain with 6-{2-Amino-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1H-indazol-3-amine

Summary for 3QCX

• Entry DOI: 10.2210/pdb3qcx/pdb
• Related: 3NUN 3NUS 3NUU 3NUY 3QCQ 3QCS 3QCY 3QD0 3QD3 3QD4
• Descriptor: 3-phosphoinositide-dependent protein kinase 1, GLYCEROL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: kinase domain, agc kinase, signal transduction, phosphorylation on s241, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: O15530
• Total number of polymer chains: 1
• Total formula weight: 37015.07

Authors

Medina, J.R.,Becker, C.J.,Blackledge, C.W.,Duquenne, C.,Feng, Y.,Grant, S.W.,Heerding, D.,Li, W.H.,Miller, W.H.,Romeril, S.P.,Scherzer, D.,Shu, A.,Bobko, M.A.,Chadderton, A.R.,Dumble, M.,Gradiner, C.M.,Gilbert, S.,Liu, Q.,Rabindran, S.K.,Sudakin, V.,Xiang, H.,Brady, P.G.,Campobasso, N.,Ward, P.,Axten, J.M. (deposition date: 2011-01-17, release date: 2011-03-09, Last modification date: 2024-11-20)

Primary citation

Medina, J.R.,Becker, C.J.,Blackledge, C.W.,Duquenne, C.,Feng, Y.,Grant, S.W.,Heerding, D.,Li, W.H.,Miller, W.H.,Romeril, S.P.,Scherzer, D.,Shu, A.,Bobko, M.A.,Chadderton, A.R.,Dumble, M.,Gardiner, C.M.,Gilbert, S.,Liu, Q.,Rabindran, S.K.,Sudakin, V.,Xiang, H.,Brady, P.G.,Campobasso, N.,Ward, P.,Axten, J.M.
Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors.
J.Med.Chem., 54:1871-1895, 2011

PubMed Abstract: Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.

PubMed: 21341675
DOI: 10.1021/jm101527u

Experimental method

X-RAY DIFFRACTION (2.3 Å)