3FDN
Structure-based drug design of novel Aurora kinase A inhibitors: Structure basis for potency and specificity
Summary for 3FDN
Entry DOI | 10.2210/pdb3fdn/pdb |
Descriptor | Serine/threonine-protein kinase 6, N-[3-(acetylamino)phenyl]-5-{(2E)-2-[(4-methoxyphenyl)methylidene]hydrazino}-3-methyl-1H-pyrazole-4-carboxamide (3 entities in total) |
Functional Keywords | aurora kinase inhibitors, virtual screening, x-ray co-crystal analysis, structure-based drug design (sbdd), h-bonding., atp-binding, cell cycle, kinase, nucleotide-binding, phosphoprotein, polymorphism, serine/threonine-protein kinase, transferase |
Biological source | Homo sapiens (human) |
Cellular location | Cytoplasm, cytoskeleton, centrosome: O14965 |
Total number of polymer chains | 1 |
Total formula weight | 32765.56 |
Authors | Leou, J.S.,Wu, J.S.,Coumar, M.S.,Shukla, P.,Hsieh, H.P.,Wu, S.Y. (deposition date: 2008-11-26, release date: 2009-09-15, Last modification date: 2023-11-01) |
Primary citation | Coumar, M.S.,Leou, J.S.,Shukla, P.,Wu, J.S.,Dixit, A.K.,Lin, W.H.,Chang, C.Y.,Lien, T.W.,Tan, U.K.,Chen, C.H.,Hsu, J.T.A.,Chao, Y.S.,Wu, S.Y.,Hsieh, H.P. Structure-based drug design of novel Aurora kinase A inhibitors: structural basis for potency and specificity J.Med.Chem., 52:1050-1062, 2009 Cited by PubMed Abstract: Aurora kinases have emerged as attractive targets for the design of anticancer drugs. Through structure-based virtual screening, novel pyrazole hit 8a was identified as Aurora kinase A inhibitor (IC(50) = 15.1 microM). X-ray cocrystal structure of 8a in complex with Aurora A protein revealed the C-4 position ethyl carboxylate side chain as a possible modification site for improving the potency. On the basis of this insight, bioisosteric replacement of the ester with amide linkage and changing the ethyl substituent to hydrophobic 3-acetamidophenyl ring led to the identification of 12w with a approximately 450-fold improved Aurora kinase A inhibition potency (IC(50) = 33 nM), compared to 8a. Compound 12w showed selective inhibition of Aurora A kinase over Aurora B/C, which might be due to the presence of a unique H-bond interaction between the 3-acetamido group and the Aurora A nonconserved Thr217 residue, which in Aurora B/C is Glu and found to sterically clash with the 3-acetamido group in modeling studies. PubMed: 19140666DOI: 10.1021/jm801270e PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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