1PXO

HUMAN CYCLIN DEPENDENT KINASE 2 COMPLEXED WITH THE INHIBITOR [4-(2-Amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine

1PXO の概要

• エントリーDOI: 10.2210/pdb1pxo/pdb
• 関連するPDBエントリー: 1AQ1 1B39 1CKP 1DI8 1DM2 1E1V 1E1X 1E9H 1FIN 1FVT 1FVV 1G5S 1GIH 1GII 1GIJ 1GZ8 1HCK 1HCL 1JSV 1JVP 1KE5 1KE6 1KE7 1KE8 1KE9 1PXM 1PXN 1PXP
• 分子名称: Cell division protein kinase 2, [4-(2-AMINO-4-METHYL-THIAZOL-5-YL)-PYRIMIDIN-2-YL]-(3-NITRO-PHENYL)-AMINE (3 entities in total)
• 機能のキーワード: protein kinase, cell cycle, phosphorylation, cell division, mitosis, inhibition, transferase, serine/threonine-protein kinase, atp-binding, 3d-structure.
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34304.84

構造登録者

Wang, S.,Meades, C.,Wood, G.,Osnowski, A.,Anderson, S.,Yuill, R.,Thomas, M.,Mezna, M.,Jackson, W.,Midgley, C.,Griffiths, G.,McNae, I.,Wu, S.Y.,McInnes, C.,Zheleva, D.,Walkinshaw, M.D.,Fischer, P.M. (登録日: 2003-07-04, 公開日: 2004-04-13, 最終更新日: 2023-08-16)

主引用文献

Wang, S.,Meades, C.,Wood, G.,Osnowski, A.,Anderson, S.,Yuill, R.,Thomas, M.,Mezna, M.,Jackson, W.,Midgley, C.,Griffiths, G.,Fleming, I.,Green, S.,McNae, I.,Wu, S.Y.,McInnes, C.,Zheleva, D.,Walkinshaw, M.D.,Fischer, P.M.
2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity.
J.Med.Chem., 47:1662-1675, 2004

PubMed Abstract: Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM K(i)s against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition.

PubMed: 15027857
DOI: 10.1021/jm0309957

実験手法

X-RAY DIFFRACTION (1.96 Å)