PDBsum entry 2b54

Transferase

PDB id: 2b54

Contents

Protein chain

298 a.a. *

Ligands

D05

Waters ×318

* Residue conservation analysis

PDB id:

2b54

Name:

Transferase

Title:

Human cyclin dependent kinase 2 (ckd2)complexed with din-232305

Structure:

Cell division protein kinase 2. Chain: a. Synonym: p33 protein kinase, cdk2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

1.85Å R-factor: 0.158 R-free: 0.263

Authors:

C.-C.Chang

Key ref:

J.A.Markwalder et al. (2004). Synthesis and biological evaluation of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of cyclin-dependent kinases. J Med Chem, 47, 5894-5911. PubMed id: 15537345 DOI: 10.1021/jm020455u

Date:

27-Sep-05 Release date: 11-Oct-05

Protein chain

P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2 from Homo sapiens

Seq: 298 a.a.

Struc: 298 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.22 - cyclin-dependent kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm020455u

J Med Chem 47:5894-5911 (2004)

PubMed id: 15537345

Synthesis and biological evaluation of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of cyclin-dependent kinases.

J.A.Markwalder, M.R.Arnone, P.A.Benfield, M.Boisclair, C.R.Burton, C.H.Chang, S.S.Cox, P.M.Czerniak, C.L.Dean, D.Doleniak, R.Grafstrom, B.A.Harrison, R.F.Kaltenbach, D.A.Nugiel, K.A.Rossi, S.R.Sherk, L.M.Sisk, P.Stouten, G.L.Trainor, P.Worland, S.P.Seitz.

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.