4ZS0

Human Aurora A catalytic domain bound to SB-6-OH

4ZS0 の概要

• エントリーDOI: 10.2210/pdb4zs0/pdb
• 分子名称: Aurora kinase A, 5-hydroxy-1'H-1,2'-bibenzimidazol-2(3H)-one (2 entities in total)
• 機能のキーワード: aurora, kinase, inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome : O14965
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33215.04

構造登録者

Marcaida, M.J.,Kilchmann, F.,Schick, T.,Reymond, J.L. (登録日: 2015-05-12, 公開日: 2016-07-20, 最終更新日: 2024-01-10)

主引用文献

Kilchmann, F.,Marcaida, M.J.,Kotak, S.,Schick, T.,Boss, S.D.,Awale, M.,Gonczy, P.,Reymond, J.L.
Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening.
J.Med.Chem., 59:7188-7211, 2016

PubMed Abstract: Here we report the discovery of a selective inhibitor of Aurora A, a key regulator of cell division and potential anticancer target. We used the atom category extended ligand overlap score (xLOS), a 3D ligand-based virtual screening method recently developed in our group, to select 437 shape and pharmacophore analogs of reference kinase inhibitors. Biochemical screening uncovered two inhibitor series with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division defects. This phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor furthermore does not induce Aurora B specific effects in cells.

PubMed: 27391133
DOI: 10.1021/acs.jmedchem.6b00709

実験手法

X-RAY DIFFRACTION (3 Å)