Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase

被引：22

作者：

Dominick, PK ^{[1
]}

Keppler, BR ^{[1
]}

Legassie, JD ^{[1
]}

Moon, IK ^{[1
]}

Jarstfer, MB ^{[1
]}

机构：

[1] Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 13期

关键词：

RNA-binding ligands; aminoglycosides; Hoechst; 33258;

D O I：

10.1016/j.bmcl.2004.04.055

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We screened a small library of known nucleic acid-binding ligands in order to identify novel inhibitors of recombinant human telomerase. Inhibitory compounds were classified into two groups: Group I inhibitors had a notably greater effect when added prior to telomerase assemblage and Group II inhibitors displayed comparable inhibition when added before or after telomerase assemblage. Hoechst 33258, a Group I inhibitor, was found to interact tightly (K-D = 0.36 muM) with human telomerase RNA (hTR) leading us to propose that hTR is the molecular target for this and other Group I inhibitors. Our results suggest that hTR can be exploited as a small-molecule drug target and provide several new structural motifs for the further development of novel telomerase inhibitors. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：3467 / 3471

页数：5

共 20 条

[1] Reconstitution of human telomerase activity in vitro [J].

Beattie, TL ;

Zhou, W ;

Robinson, MO ;

Harrington, L .

CURRENT BIOLOGY, 1998, 8 (03) :177-180

[2]

Beltz L. A., 2002, Current Medicinal Chemistry - Anti-Cancer Agents, V2, P589, DOI 10.2174/1568011023353831

[3] A mutant of Tetrahymena telomerase reverse transcriptase with increased processivity [J].

Bryan, TM ;

Goodrich, KJ ;

Cech, TR .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (31) :24199-24207

[4] Beginning to understand the end of the chromosome [J].

Cech, TR .

CELL, 2004, 116 (02) :273-279

[5] Specific binding of Hoechst 33258 to site 1 thymidylate synthase mRNA [J].

Cho, J ;

Rando, RR .

NUCLEIC ACIDS RESEARCH, 2000, 28 (10) :2158-2163

[6] Telomerase inhibition, oligonucleotides, and clinical trials [J].

Corey, DR .

ONCOGENE, 2002, 21 (04) :631-637

[7] The Design of G-quadruplex Ligands as Telomerase Inhibitors [J].

Cuesta, Javier ;

Read, Martin A. ;

Neidle, Stephen .

MINI-REVIEWS IN MEDICINAL CHEMISTRY, 2003, 3 (01) :11-21

[8] A highly selective telomerase inhibitor limiting human cancer cell proliferation [J].

Damm, K ;

Hemmann, U ;

Garin-Chesa, P ;

Hauel, N ;

Kauffmann, I ;

Priepke, H ;

Niestroj, C ;

Daiber, C ;

Enenkel, B ;

Guilliard, B ;

Lauritsch, I ;

Müller, E ;

Pascolo, E ;

Sauter, G ;

Pantic, M ;

Martens, UM ;

Wenz, C ;

Lingner, J ;

Kraut, N ;

Rettig, WJ ;

Schnapp, A .

EMBO JOURNAL, 2001, 20 (24) :6958-6968

[9] Binding of Hoechst 33258 to the TAR RNA of HIV-1. Recognition of a pyrimidine bulge-dependent structure [J].

Dassonneville, L ;

Hamy, F ;

Colson, P ;

Houssier, C ;

Bailly, C .

NUCLEIC ACIDS RESEARCH, 1997, 25 (22) :4487-4492

[10] Protection of mammalian telomeres [J].

de Lange, T .

ONCOGENE, 2002, 21 (04) :532-540

← 1 2 →