2BPM

STRUCTURE OF CDK2-CYCLIN A WITH PHA-630529

Summary for 2BPM

• Entry DOI: 10.2210/pdb2bpm/pdb
• Related: 1AQ1 1B38 1B39 1BUH 1CKP 1DI8 1DM2 1E1V 1E1X 1E9H 1F5Q 1FIN 1FQ1 1FVT 1FVV 1G5S 1GIH 1GII 1GIJ 1GY3 1GZ8 1H00 1H01 1H07 1H08 1H0V 1H0W 1H1P 1H1Q 1H1R 1H1S 1H24 1H25 1H26 1H27 1H28 1HCK 1HCL 1JST 1JSU 1JSV 1JVP 1KE5 1KE6 1KE7 1KE8 1KE9 1OGU 1OI9 1OIQ 1OIR 1OIT 1OIU 1OIY 1OKU 1OKV 1OKW 1OL1 1OL2 1P2A 1P5E 1PF8 1PKD 1PW2 1PXI 1PXJ 1PXK 1PXL 1PXM 1PXN 1PXO 1PXP 1PYE 1QMZ 1R78 1URC 1URW 1V1K 1VYW 1VYZ 1W0X 1W8C 1W98 1WCC 1Y8Y 1Y91 2B52 2B53 2B54 2B55 2BHE 2BHH 2BKZ 2BTR 2BTS 2C4G 2C5N 2C5O 2C5P 2C5T 2C5V 2C5X 2C5Y 2C68 2C69 2C6I 2C6K 2C6L 2C6M 2C6O 2C6T
• Descriptor: CELL DIVISION PROTEIN KINASE 2, CYCLIN A2, (2S)-N-[(3Z)-5-CYCLOPROPYL-3H-PYRAZOL-3-YLIDENE]-2-[4-(2-OXOIMIDAZOLIDIN-1-YL)PHENYL]PROPANAMIDE, ... (5 entities in total)
• Functional Keywords: protein kinase, transferase, serine/threonine-protein kinase, phosphorylation, cell division, cyclin
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 4
• Total formula weight: 131928.58

Authors

Cameron, A.,Fogliatto, G.,Pevarello, P.,Brasca, M.G.,Orsini, P.,Traquandi, G.,Longo, A.,Nesi, M.,Orzi, F.,Piutti, C.,Sansonna, P.,Varasi, M.,Vulpetti, A.,Roletto, F.,Alzani, R.,Ciomei, M.,Albanese, C.,Pastori, W.,Marsiglio, A.,Pesenti, E.,Fiorentini, F.,Bischoff, J.R.,Mercurio, C. (deposition date: 2005-04-21, release date: 2005-12-08, Last modification date: 2023-12-13)

Primary citation

Pevarello, P.,Brasca, M.G.,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, J.R.,Mercurio, C.
3-Aminopyrazole Inhibitors of Cdk2-Cyclin a as Antitumor Agents. 2. Lead Optimization
J.Med.Chem., 48:2944-, 2005

PubMed 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.

PubMed: 15828833
DOI: 10.1021/JM0408870

Experimental method

X-RAY DIFFRACTION (2.4 Å)