A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex

Marchand, Christophe; Antony, Smitha; Kohn, Kurt W.; Cushman, Mary; Ioanoviciu, Alexandra; Staker, Bart L.; Burgin, Alex B.; Stewart, Lance; Pommier, ﻿Yves

doi:10.1158/1535-7163.mct-05-0456

Cited by 153 publications

(134 citation statements)

References 61 publications

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“…1A). Based on the crystal structure, there exists a structural overlap between CPT and the indenoisoquinolines in their interaction with Top1-DNA complexes (14)(15)(16). Structural similarity could account for the trapping of DNA-Top1 cleavage complexes at similar sites between CPT and the indenoisoquinolines NSC 725776, NSC 724998, and NSC 706744 (sites 70, 92, 97, and 119; Fig.…”

Section: Discussionmentioning

confidence: 99%

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Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance

et al. 2007

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Camptothecin (CPT) derivatives are effective anticancer drugs, especially against solid tumors. As CPTs are chemically unstable and have clinical limitations, we have synthesized indenoisoquinolines as novel topoisomerase I (Top1) inhibitors. We presently report two indenoisoquinoline derivatives, NSC 725776 and NSC 724998, which have been selected for therapeutic development. Both are potent Top1 inhibitors and induce Top1 cleavage at unique genomic positions compared with CPT. Consistent with Top1 poisoning, protein-linked DNA breaks were detected in cells treated with NSC 725776 and NSC 724998 at nanomolar concentrations. Those druginduced protein-linked DNA breaks persisted longer after drug removal than those produced by CPT. Studies in human cells in culture show that NSC 725776 and NSC 724998 exert antiproliferative activity at submicromolar concentrations. Furthermore, NSC 725776 and NSC 724998 show crossresistance in cells deficient or silenced for Top1, which is consistent with their selective Top1 targeting. Similar to other known Top1 inhibitors, NSC 725776-treated and NSC 724998-treated cells show an arrest of cell cycle progression in both S and G 2 -M and a dependence on functional p53 for their cytotoxicity. Dose-dependent ;-H2AX foci formation was readily observed in cells treated with NSC 725776 and NSC 724998. These ;-H2AX foci were detectable at pharmacologically relevant doses for up to 24 h and thus could be used as biomarkers for clinical trials (phase 0). [Cancer Res 2007; 67(21):10397-405]

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Section: Discussionmentioning

confidence: 99%

“…We have now synthesized and tested >300 indenoisoquinoline derivatives and found that some of them are both very potent Top1 poisons and exhibit antitumor activity in mouse models (10)(11)(12)(13). We have also obtained crystal structures of two different indenoisoquinolines within Top1 cleavage complexes (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance

et al. 2007

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“…Threedimensional structure analyses of a ternary complex formed between Top1, DNA, and CPT or topotecan by X-ray crystallography (6,11) showed that one drug molecule interacts both with the DNA base pairs flanking the cleavage sites and three key amino acid residues of Top1 (Asn 722 , Arg 364 , and Asp 533 ; ref. 12). Single mutation of any of those three amino acid residues is sufficient to confer high resistance to CPT and its analogues (13).…”

Section: Introductionmentioning

confidence: 99%

“…The E-ring of CPT (Fig. 1A) is essential to the interaction of the drug with the Top1-DNA cleavage complex (6,11,12). Because CPT analogues are the only clinical drugs targeting Top1, and because of their clinical importance, the search for novel inhibitors of Top1 is ongoing (2).…”

Section: Introductionmentioning

confidence: 99%

Novel E-ring camptothecin keto analogues (S38809 and S39625) are stable, potent, and selective topoisomerase I inhibitors without being substrates of drug efflux transporters

Takagi

Dexheimer

Redon

et al. 2007

Molecular Cancer Therapeutics

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Camptothecin (CPT) analogues are powerful anticancer agents but are chemically unstable due to their A-hydroxylactone six-membered E-ring structure, which is essential for trapping topoisomerase I (Top1)-DNA cleavage complexes. To stabilize the E-ring, CPT keto analogues with a five-membered E-ring lacking the oxygen of the lactone ring (S38809 and S39625) have been synthesized. S39625 has been selected for advanced preclinical development based on its promising activity in tumor models. Here, we show that both keto analogues are active against purified Top1 and selective against Top1 in yeast and human cancer cells. The keto analogues show improved cytotoxicity toward colon, breast, and prostate cancer cells and leukemia cells compared with CPT. The drug-induced Top1-DNA cleavage complexes induced by the keto analogues show remarkable persistence both with purified Top1 and in cells following 1-h drug treatments. Moreover, we find that S39625 is not a substrate for either the ABCB1 (multidrug resistance-1/P-glycoprotein) or ABCG2 (mitoxantrone resistance/ breast cancer resistance protein) drug efflux transporters, which sets S39625 apart from the clinically used CPT analogues topotecan or SN-38 (active metabolite of irinotecan). Finally, we show that nanomolar concentrations of S38809 or S39625 induce intense and persistent histone ;-H2AX. The chemical stability of the keto analogues and the ability of S39625 to produce high levels of persistent Top1-DNA cleavage complex and its potent antiproliferative activity against human cancer cell lines make S39625 a promising new anticancer drug candidate. Histone ;-H2AX could be used as a biomarker for the upcoming clinical trials of S39625. [Mol Cancer Ther 2007;6(12):3229 -38]

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“…Under physiological conditions (pH 7.2-7.4) the carboxylate form predominates. However only the lactone form of these compounds is responsible for their biological activity to interact with the topoisomerase-I and DNA complex (Hertzberg et al, 1989;Capranico et al, 2007;Marchand et al, 2006). The structures of topotecan and irinotecan and pH-dependent conversions are shown in Figure 1-1. …”

Section: Camptothecin Analogsmentioning

confidence: 99%

Factors Influencing Topotecan CNS Penetration in Mouse Models

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A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex

Cited by 153 publications

References 61 publications

Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance

Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance

Novel E-ring camptothecin keto analogues (S38809 and S39625) are stable, potent, and selective topoisomerase I inhibitors without being substrates of drug efflux transporters

Factors Influencing Topotecan CNS Penetration in Mouse Models

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