2B54

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

Summary for 2B54

• Entry DOI: 10.2210/pdb2b54/pdb
• Related: 2B52 2B53 2B55
• Descriptor: 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)
• Functional Keywords: protein kinase, cell cycle, phosphorylation, cell division, mitosis, inhibition, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34442.20

Authors

Chang, C.-C. (deposition date: 2005-09-27, release date: 2005-10-11, Last modification date: 2024-04-03)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.85 Å)