2B54

Human cyclin dependent kinase 2 (CKD2)complexed with DIN-232305

2B54 の概要

• エントリーDOI: 10.2210/pdb2b54/pdb
• 関連するPDBエントリー: 2B52 2B53 2B55
• 分子名称: Cell division protein kinase 2, 6-(3,4-DIHYDROXYBENZYL)-3-ETHYL-1-(2,4,6-TRICHLOROPHENYL)-1H-PYRAZOLO[3,4-D]PYRIMIDIN-4(5H)-ONE (3 entities in total)
• 機能のキーワード: protein kinase, cell cycle, phosphorylation, cell division, mitosis, inhibition, 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: 34442.20

構造登録者

Chang, C.-C. (登録日: 2005-09-27, 公開日: 2005-10-11, 最終更新日: 2024-04-03)

主引用文献

Markwalder, J.A.,Arnone, M.R.,Benfield, P.A.,Boisclair, M.,Burton, C.R.,Chang, C.-C.,Cox, S.S.,Czerniak, P.M.,Dean, C.L.,Dolenaik, D.,Grafstrom, R.,Harrison, B.A.,Kaltenbach III, R.F.,Nugiel, D.A.,Rossi, K.A.,Sherk, S.R.,Sisk, L.M.,Stouten, P.,Trainor, G.L.,Worland, P.,Seitz, S.P.
Synthesis and biological evaluation of 1-aryl-4,5-dihydro-1h-pyraxolo[3,4-d]pyrimidin-4-one inhibitors of cyclin dependent kinases
J.Med.Chem., 47:5894-5911, 2004

PubMed Abstract: Using a high-throughput screening strategy, a series of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-ones was identified that inhibit the cyclin-dependent kinase (CDK) 4/cyclin D1 complex-mediated phosphorylation of a protein substrate with IC(50)s in the low micromolar range. On the basis of preliminary structure-activity relationships (SAR), a model was proposed in which these inhibitors occupy the ATP-binding site of the enzyme, forming critical hydrogen bonds to the same residue (Val96) to which the amino group in ATP is presumed to bind. X-ray diffraction studies on a later derivative bound to CDK2 support this binding mode. Iterative cycles of synthesis and screening lead to a novel series of potent, CDK2-selective 6-(arylmethyl)pyrazolopyrimidinones. Placement of a hydrogen-bond donor in the meta-position on the 6-arylmethyl group resulted in approximately 100-fold increases in CDK4 affinity, giving ligands that were equipotent inhibitors of CDK4 and CDK2. These compounds exhibit antiproliferative effects in the NCI HCT116 and other cell lines. The potency of these antiproliferative effects is enhanced in anilide derivatives and translates into tumor growth inhibition in a mouse xenograft model.

PubMed: 15537345
DOI: 10.1021/jm020455u

実験手法

X-RAY DIFFRACTION (1.85 Å)