3PJ8

Structure of CDK2 in complex with a Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine.

3PJ8 の概要

• エントリーDOI: 10.2210/pdb3pj8/pdb
• 関連するPDBエントリー: 1G5S 1W0X 2A0C 2A4L 3DDP 3DDQ
• 分子名称: Cell division protein kinase 2, (2R)-2-{[7-(benzylamino)-3-(propan-2-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]amino}butan-1-ol (3 entities in total)
• 機能のキーワード: phosphorylation, cell division, mitosis, cyclin, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 34387.99

構造登録者

McNae, I.W.,Jorda, R.,Havlicek, L.,Strnad, M.,Voller, J.,Walkinshaw, M.D.,Krystof, V. (登録日: 2010-11-09, 公開日: 2011-04-06, 最終更新日: 2024-02-21)

主引用文献

Jorda, R.,McNae, I.W.,Walkinshaw, M.D.,Voller, J.,Navratilova, J.,Kuzma, M.,Mistrik, M.,Bartek, J.,Strnad, M.
Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative Activity.
J.Med.Chem., 54:2980-2993, 2011

PubMed Abstract: Inhibition of cyclin-dependent kinases (CDKs) with small molecules has been suggested as a strategy for treatment of cancer, based on deregulation of CDKs commonly found in many types of human tumors. Here, a new potent CDK2 inhibitor with pyrazolo[4,3-d]pyrimidine scaffold has been synthesized, characterized, and evaluated in cellular and biochemical assays. 7-Benzylamino-5(R)-[2-(hydroxymethyl)propyl]amino-3-isopropyl-1(2)H-pyrazolo[4,3-d]pyrimidine, compound 7, was prepared as a bioisostere of the well-known CDK inhibitor roscovitine. An X-ray crystal structure of compound 7 bound to CDK2 has been determined, revealing a binding mode similar to that of roscovitine. Protein kinase selectivity profile of compound 7 and its biological effects (cell cycle arrest, dephosphorylation of the retinoblastoma protein, accumulation of the tumor suppressor protein p53, induction of apoptosis, inhibition of homologous recombination) are consistent with CDK inhibition as a primary mode of action. Importantly, as the anticancer activities of the pyrazolo[4,3-d]pyrimidine 7 exceed those of its bioisostere roscovitine, compound 7 reported here may be preferable for cancer therapy.

PubMed: 21417417
DOI: 10.1021/jm200064p

実験手法

X-RAY DIFFRACTION (1.96 Å)