1VYW

Structure of CDK2/Cyclin A with PNU-292137

Summary for 1VYW

• Entry DOI: 10.2210/pdb1vyw/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 1H06 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 1QMZ 1R78 1URC 1URW 1V1K
• Descriptor: CELL DIVISION PROTEIN KINASE 2, CYCLIN A2, SULFATE ION, ... (5 entities in total)
• Functional Keywords: transferase-complex, protein kinase-complex, 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: 131836.52

Authors

Pevarello, P.,Brasca, M.G.,Amici, R.,Orsini, P.,Traquandi, G.,Corti, L.,Piutti, C.,Sansonna, P.,Villa, M.,Pierce, B.S.,Pulici, M.,Giordano, P.,Martina, K.,Fritzen, E.L.,Nugent, R.A.,Casale, E.,Cameron, A.,Ciomei, M.,Roletto, F.,Isacchi, A.,Fogliatto, G.,Pesenti, E.,Pastori, W.,Marsiglio, A.,Leach, K.L.,Clare, P.M.,Fiorentini, F.,Varasi, M.,Vulpetti, A.,Warpehoski, M.A. (deposition date: 2004-05-07, release date: 2004-06-10, Last modification date: 2024-05-08)

Primary citation

Pevarello, P.,Brasca, M.G.,Amici, R.,Orsini, P.,Traquandi, G.,Corti, L.,Piutti, C.,Sansonna, P.,Villa, M.,Pierce, B.S.,Pulici, M.,Giordano, P.,Martina, K.,Fritzen, E.L.,Nugent, R.A.,Casale, E.,Cameron, A.,Ciomei, M.,Roletto, F.,Isacchi, A.,Fogliatto, G.,Pesenti, E.,Pastori, W.,Marsiglio, A.,Leach, K.L.,Clare, P.M.,Fiorentini, F.,Varasi, M.,Vulpetti, A.,Warpehoski, M.A.
3-Aminopyrazole Inhibitors of Cdk2/Cyclin a as Antitumor Agents. Part 1. Lead Finding
J.Med.Chem., 47:3367-, 2004

PubMed Abstract: Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.

PubMed: 15189033
DOI: 10.1021/JM031145U

Experimental method

X-RAY DIFFRACTION (2.3 Å)