3FDN

Structure-based drug design of novel Aurora kinase A inhibitors: Structure basis for potency and specificity

3FDN の概要

• エントリーDOI: 10.2210/pdb3fdn/pdb
• 分子名称: 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)
• 機能のキーワード: 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
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton, centrosome: O14965
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32765.56

構造登録者

Leou, J.S.,Wu, J.S.,Coumar, M.S.,Shukla, P.,Hsieh, H.P.,Wu, S.Y. (登録日: 2008-11-26, 公開日: 2009-09-15, 最終更新日: 2023-11-01)

主引用文献

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

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: 19140666
DOI: 10.1021/jm801270e

実験手法

X-RAY DIFFRACTION (1.9 Å)