PDBsum entry 2bpm

Transferase

PDB id: 2bpm

Contents

Protein chains

302 a.a. *

258 a.a. *

Ligands

529 ×2

SO4 ×2

Waters ×414

* Residue conservation analysis

PDB id:

2bpm

Name:

Transferase

Title:

Structure of cdk2-cyclin a with pha-630529

Structure:

Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase. Engineered: yes. Cyclin a2. Chain: b, d. Fragment: residues 174-432 (c-terminal portion). Synonym: cyclin a. 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.

Biol. unit:

Dimer (from PDB file)

Resolution:

2.40Å R-factor: 0.229 R-free: 0.271

Authors:

A.Cameron,G.Fogliatto,P.Pevarello,M.G.Brasca,P.Orsini,G.Traquandi, A.Longo,M.Nesi,F.Orzi,C.Piutti,P.Sansonna,M.Varasi,A.Vulpetti, F.Roletto,R.Alzani,M.Ciomei,C.Albanese,W.Pastori,A.Marsiglio, E.Pesenti,F.Fiorentini,J.R.Bischoff,C.Mercurio

Key ref:

P.Pevarello et al. (2005). 3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 2. Lead optimization. J Med Chem, 48, 2944-2956. PubMed id: 15828833 DOI: 10.1021/jm0408870

Date:

21-Apr-05 Release date: 08-Dec-05

Protein chains

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

Seq: 298 a.a.

Struc: 302 a.a.

Protein chains

P20248  (CCNA2_HUMAN) -  Cyclin-A2 from Homo sapiens

Seq: 432 a.a.

Struc: 258 a.a.

Enzyme reactions

• Enzyme class: 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⁺

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

reference

DOI no: 10.1021/jm0408870

J Med Chem 48:2944-2956 (2005)

PubMed id: 15828833

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 2. Lead optimization.

P.Pevarello, M.G.Brasca, P.Orsini, G.Traquandi, A.Longo, M.Nesi, F.Orzi, C.Piutti, P.Sansonna, M.Varasi, A.Cameron, A.Vulpetti, F.Roletto, R.Alzani, M.Ciomei, C.Albanese, W.Pastori, A.Marsiglio, E.Pesenti, F.Fiorentini, J.R.Bischoff, C.Mercurio.

ABSTRACT

Inhibitors of cyclin-dependent kinases (CDK) such as CDK2/cyclin A-E are currently undergoing clinical trials to verify their potential as new anticancer agents. In a previous article we described the lead discovery process of a 3-aminopyrazole class of CDK2/cyclin A-E inhibitors. The endpoint of this process was PNU-292137, a compound endowed with in vivo antitumor activity in a mouse tumor xenograft model. We optimized this lead compound to improve some physicochemical properties, notably solubility and plasma protein binding. This lead optimization process brought us to the discovery of (2S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(2-oxo-1-pyrrolidinyl)phenyl]propanamide (PHA-533533, 13), a compound with a balanced activity vs druglike profile. Compound 13 inhibited CDK2/cyclin A with a K(i) of 31 nM, counteracting tumor cell proliferation of different cell lines with an IC(50) in the submicromolar range. Solubility was improved more than 10 times over the starting lead, while plasma protein binding was decreased from 99% to 74%. With exploitation of this globally enhanced in vitro profile, 13 was more active than PNU-292137 in vivo in the A2780 xenograft model showing a tumor growth inhibition of 70%. Proof of mechanism of action was obtained in vivo by immunohistochemical analysis of tumor slices of 13-treated vs untreated animals.