1PYE

Crystal structure of CDK2 with inhibitor

1PYE の概要

• エントリーDOI: 10.2210/pdb1pye/pdb
• 関連するPDBエントリー: 1PY5
• 分子名称: Cell division protein kinase 2, [2-AMINO-6-(2,6-DIFLUORO-BENZOYL)-IMIDAZO[1,2-A]PYRIDIN-3-YL]-PHENYL-METHANONE (3 entities in total)
• 機能のキーワード: cdk, cyclin-dependent kinase 2, transferase
• 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: 34353.83

構造登録者

Zhang, F.,Hamdouchi, C. (登録日: 2003-07-08, 公開日: 2004-07-13, 最終更新日: 2024-02-14)

主引用文献

Hamdouchi, C.,Keyser, H.,Collins, E.,Jaramillo, C.,De Diego, J.E.,Spencer, C.D.,Dempsey, J.A.,Anderson, B.D.,Leggett, T.,Stamm, N.B.,Schultz, R.M.,Watkins, S.A.,Cocke, K.,Lemke, S.,Burke, T.F.,Beckmann, R.P.,Dixon, J.T.,Gurganus, T.M.,Rankl, N.B.,Houck, K.A.,Zhang, F.,Vieth, M.,Espinosa, J.,Timm, D.E.,Campbell, R.M.,Patel, B.K.,Brooks, H.B.
The discovery of a new structural class of cyclin-dependent kinase inhibitors, aminoimidazo[1,2-a]pyridines.
MOL.CANCER THER., 3:1-9, 2004

PubMed Abstract: The protein kinase family represents an enormous opportunity for drug development. However, the current limitation in structural diversity of kinase inhibitors has complicated efforts to identify effective treatments of diseases that involve protein kinase signaling pathways. We have identified a new structural class of protein serine/threonine kinase inhibitors comprising an aminoimidazo[1,2-a]pyridine nucleus. In this report, we describe the first successful use of this class of aza-heterocycles to generate potent inhibitors of cyclin-dependent kinases that compete with ATP for binding to a catalytic subunit of the protein. Co-crystal structures of CDK2 in complex with lead compounds reveal a unique mode of binding. Using this knowledge, a structure-based design approach directed this chemical scaffold toward generating potent and selective CDK2 inhibitors, which selectively inhibited the CDK2-dependent phosphorylation of Rb and induced caspase-3-dependent apoptosis in HCT 116 tumor cells. The discovery of this new class of ATP-site-directed protein kinase inhibitors, aminoimidazo[1,2-a]pyridines, provides the basis for a new medicinal chemistry tool to be used in the search for effective treatments of cancer and other diseases that involve protein kinase signaling pathways.

PubMed: 14749470

実験手法

X-RAY DIFFRACTION (2 Å)