PDBsum entry 2wip

Transferase

PDB id: 2wip

Contents

Protein chains

297 a.a. *

258 a.a. *

Ligands

P49 ×2

SO4

Waters ×172

* Residue conservation analysis

PDB id:

2wip

Name:

Transferase

Title:

Structure of cdk2-cyclin a complexed with 8-anilino-1-methyl-4,5- dihydro- 1h-pyrazolo[4,3-h] quinazoline-3-carboxylic acid

Structure:

Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase. Engineered: yes. Cyclin-a2. Chain: b, d. Fragment: c-terminal portion, residues 173-432. Synonym: cyclin-a, cyclin a2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: high five. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.

Resolution:

2.80Å R-factor: 0.221 R-free: 0.258

Authors:

M.G.Brasca,N.Amboldi,D.Ballinari,A.D.Cameron,E.Casale,G.Cervi, M.Colombo,F.Colotta,V.Croci,R.Dalessio,F.Fiorentini,A.Isacchi, C.Mercurio,W.Moretti,A.Panzeri,W.Pastori,P.Pevarello,F.Quartieri, F.Roletto,G.Traquandi,P.Vianello,A.Vulpetti,M.Ciomei

Key ref:

M.G.Brasca et al. (2009). Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J Med Chem, 52, 5152-5163. PubMed id: 19603809

Date:

14-May-09 Release date: 28-Jul-09

Protein chains

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

Seq: 298 a.a.

Struc: 297 a.a.

Protein chains

P20248  (CCNA2_HUMAN) -  Cyclin-A2 from Homo sapiens

Seq: 432 a.a.

Struc: 258 a.a.

Enzyme reactions

• Enzyme class 1: Chains A, C: 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⁺
• Enzyme class 2: Chains B, D: E.C.?

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

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

reference

J Med Chem 52:5152-5163 (2009)

PubMed id: 19603809

Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor.

M.G.Brasca, N.Amboldi, D.Ballinari, A.Cameron, E.Casale, G.Cervi, M.Colombo, F.Colotta, V.Croci, R.D'Alessio, F.Fiorentini, A.Isacchi, C.Mercurio, W.Moretti, A.Panzeri, W.Pastori, P.Pevarello, F.Quartieri, F.Roletto, G.Traquandi, P.Vianello, A.Vulpetti, M.Ciomei.

ABSTRACT

The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.