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Titolo:
Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases
Autore:
Zaharevitz, DW; Gussio, R; Leost, M; Senderowicz, AM; Lahusen, T; Kunick, C; Meijer, L; Sausville, EA;
Indirizzi:
NCI,MDev Therapeut Program, EPN, Div Canc Treatment & Diagnosis, Bethesda,NCI Bethesda MD USA 20892 EPN, Div Canc Treatment & Diagnosis, Bethesda, CNRS, Cell Cycle Grp, F-29680 Roscoff, Bretagne, France CNRS Roscoff Bretagne France F-29680 p, F-29680 Roscoff, Bretagne, France Univ Hamburg, Inst Pharm, D-20146 Hamburg, Germany Univ Hamburg Hamburg Germany D-20146 nst Pharm, D-20146 Hamburg, Germany
Titolo Testata:
CANCER RESEARCH
fascicolo: 11, volume: 59, anno: 1999,
pagine: 2566 - 2569
SICI:
0008-5472(19990601)59:11<2566:DAICOT>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
FLAVOPIRIDOL; IDENTIFICATION; DEHYDROGENASE; CYTOTOXICITY; ROSCOVITINE; POTENT; CDK2; CDC2;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
20
Recensione:
Indirizzi per estratti:
Indirizzo: Zaharevitz, DW NCI,6130 Therapeut Program, EPN, Div Canc Treatment & Diagnosis, Suite 811, NCI Suite 811,6130 Execut Blvd,MSC 7444 Bethesda MD USA 20892
Citazione:
D.W. Zaharevitz et al., "Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases", CANCER RES, 59(11), 1999, pp. 2566-2569

Abstract

Analysis of the National Cancer Institute Human Tumor Cell Line Anti-Cancer Drug Screen data using the COMPARE algorithm to detect similarities in the pattern of compound action to flavopiridol, a known inhibitor of cyclin-dependent kinases (CDKs), has suggested several possible,novel CDK inhibitors, 9-Bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one, NSC-664704 (kenpaullone), is reported here to be a potent inhibitor of CDK1/cyclin B (IC50 0.4 mu M). This compound also inhibited CDK2/cyclin A (IC50 0.68 mu M), CDK2/cyclin E (IC50 7.5 mu M), and CDK5/p25 (IC50 0.85 mu M) but had much less effect on other kinases; only c-src (IC50 15 mu M), casein-kinase 2 (IC50 20 mu M), erk 1 (IC50 20 mu M), and erk 2 (IC50 9 mu M) were inhibited with IC(50)s less than 35 mu M. Kenpaullone acts by competitive inhibition of ATP binding, Molecular modeling indicates that kenpaullone can bind in the ATP binding site of CDK2 with residue contacts similar to those observed in the crystal structures of other CDK2-bound inhibitors, Analogues of kenpaullone, in particular 10-bromopaullone (NSC-672234), also inhibited various protein kinases including CDKs, Cells exposed to kenpaullone and 10-bromopaullone display delayed cell cycle progression. Kenpaullone represents a novel chemotype:for compounds that preferentially inhibit CDKs.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 24/09/20 alle ore 00:39:19