3L9N

crystal structure of PKAB3 (pka triple mutant V123A, L173M, Q181K) with compound 27

Summary for 3L9N

• Entry DOI: 10.2210/pdb3l9n/pdb
• Related: 3L9L 3L9M
• Descriptor: cAMP-dependent protein kinase catalytic subunit alpha, cAMP-dependent protein kinase inhibitor alpha, (2S)-N~1~-[5-(1H-indazol-5-yl)-1,3,4-thiadiazol-2-yl]-3-(4-methylphenyl)propane-1,2-diamine, ... (4 entities in total)
• Functional Keywords: pkb, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm (By similarity): P17612
• Total number of polymer chains: 2
• Total formula weight: 43390.48

Authors

Huang, X. (deposition date: 2010-01-05, release date: 2011-01-19, Last modification date: 2023-09-06)

Primary citation

Zeng, Q.,Allen, J.G.,Bourbeau, M.P.,Wang, X.,Yao, G.,Tadesse, S.,Rider, J.T.,Yuan, C.C.,Hong, F.T.,Lee, M.R.,Zhang, S.,Lofgren, J.A.,Freeman, D.J.,Yang, S.,Li, C.,Tominey, E.,Huang, X.,Hoffman, D.,Yamane, H.K.,Fotsch, C.,Dominguez, C.,Hungate, R.,Zhang, X.
Azole-based inhibitors of AKT/PKB for the treatment of cancer.
Bioorg.Med.Chem.Lett., 20:1559-1564, 2010

PubMed Abstract: Through a combination of screening and structure-based rational design, we have discovered a series of N(1)-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.

PubMed: 20137943
DOI: 10.1016/j.bmcl.2010.01.067

Experimental method

X-RAY DIFFRACTION (2 Å)