2bpm

File:2bpm.gif

spinqualitylabelsall models 2bpm, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

STRUCTURE OF CDK2-CYCLIN A WITH PHA-630529

OverviewOverview

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]p, ropanamide (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.

About this StructureAbout this Structure

2BPM is a Protein complex structure of sequences from Homo sapiens with SO4 and 529 as ligands. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Structure known Active Site: AC1. Full crystallographic information is available from OCA.

ReferenceReference

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 2. Lead optimization., Pevarello P, Brasca MG, Orsini P, Traquandi G, Longo A, Nesi M, Orzi F, Piutti C, Sansonna P, Varasi M, Cameron A, Vulpetti A, Roletto F, Alzani R, Ciomei M, Albanese C, Pastori W, Marsiglio A, Pesenti E, Fiorentini F, Bischoff JR, Mercurio C, J Med Chem. 2005 Apr 21;48(8):2944-56. PMID:15828833

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