Structure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones.

2.50
Hdl Handle:
http://hdl.handle.net/10541/85599
Title:
Structure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones.
Authors:
Faig, Margarita; Bianchet, Mario A; Winski, Shannon; Hargreaves, Robert H J; Moody, Christopher J; Hudnott, Anna R; Ross, David; Amzel, L Mario
Abstract:
BACKGROUND: NAD(P)H:quinone acceptor oxidoreductase (QR1) protects animal cells from the deleterious and carcinogenic effects of quinones and other electrophiles. Remarkably, the same enzyme activates cancer prodrugs that become cytotoxic only after two-electron reduction. QR1's ability to bioactivate quinones and its elevated expression in many human solid tumors makes this protein an excellent target for enzyme-directed drug development. Until now, structural analysis of the mode of binding of chemotherapeutic compounds to QR1 was based on model building using the structures of complexes with simple substrates; no structure of complexes of QR1 with chemotherapeutic prodrugs had been reported. RESULTS: Here we report the high-resolution crystal structures of complexes of QR1 with three chemotherapeutic prodrugs: RH1, a water-soluble homolog of dimethylaziridinylbenzoquinone; EO9, an aziridinylindolequinone; and ARH019, another aziridinylindolequinone. The structures, determined to resolutions of 2.0 A, 2.5 A, and 1.86 A, respectively, were refined to R values below 21% with excellent geometry. CONCLUSIONS: The structures show that compounds can bind to QR1 in more than one orientation. Surprisingly, the two aziridinylindolequinones bind to the enzyme in different orientations. The results presented here reveal two new factors that must be taken into account in the design of prodrugs targeted for activation by QR1: the enzyme binding site is highly plastic and changes to accommodate binding of different substrates, and homologous drugs with different substituents may bind to QR1 in different orientations. These structural insights provide important clues for the optimization of chemotherapeutic compounds that utilize this reductive bioactivation pathway.
Affiliation:
Department of Biophysics and Biophysical Chemistry, Johns Hopkins Medical School, Baltimore, MD 21205, USA.
Citation:
Structure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones. 2001, 9 (8):659-67 Structure
Journal:
Structure
Issue Date:
Aug-2001
URI:
http://hdl.handle.net/10541/85599
PubMed ID:
11587640
Type:
Article
Language:
en
ISSN:
0969-2126
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorFaig, Margaritaen
dc.contributor.authorBianchet, Mario Aen
dc.contributor.authorWinski, Shannonen
dc.contributor.authorHargreaves, Robert H Jen
dc.contributor.authorMoody, Christopher Jen
dc.contributor.authorHudnott, Anna Ren
dc.contributor.authorRoss, Daviden
dc.contributor.authorAmzel, L Marioen
dc.date.accessioned2009-11-06T16:06:47Z-
dc.date.available2009-11-06T16:06:47Z-
dc.date.issued2001-08-
dc.identifier.citationStructure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones. 2001, 9 (8):659-67 Structureen
dc.identifier.issn0969-2126-
dc.identifier.pmid11587640-
dc.identifier.urihttp://hdl.handle.net/10541/85599-
dc.description.abstractBACKGROUND: NAD(P)H:quinone acceptor oxidoreductase (QR1) protects animal cells from the deleterious and carcinogenic effects of quinones and other electrophiles. Remarkably, the same enzyme activates cancer prodrugs that become cytotoxic only after two-electron reduction. QR1's ability to bioactivate quinones and its elevated expression in many human solid tumors makes this protein an excellent target for enzyme-directed drug development. Until now, structural analysis of the mode of binding of chemotherapeutic compounds to QR1 was based on model building using the structures of complexes with simple substrates; no structure of complexes of QR1 with chemotherapeutic prodrugs had been reported. RESULTS: Here we report the high-resolution crystal structures of complexes of QR1 with three chemotherapeutic prodrugs: RH1, a water-soluble homolog of dimethylaziridinylbenzoquinone; EO9, an aziridinylindolequinone; and ARH019, another aziridinylindolequinone. The structures, determined to resolutions of 2.0 A, 2.5 A, and 1.86 A, respectively, were refined to R values below 21% with excellent geometry. CONCLUSIONS: The structures show that compounds can bind to QR1 in more than one orientation. Surprisingly, the two aziridinylindolequinones bind to the enzyme in different orientations. The results presented here reveal two new factors that must be taken into account in the design of prodrugs targeted for activation by QR1: the enzyme binding site is highly plastic and changes to accommodate binding of different substrates, and homologous drugs with different substituents may bind to QR1 in different orientations. These structural insights provide important clues for the optimization of chemotherapeutic compounds that utilize this reductive bioactivation pathway.en
dc.language.isoenen
dc.subject.meshAntineoplastic Agents-
dc.subject.meshBenzoquinones-
dc.subject.meshBinding Sites-
dc.subject.meshCatalytic Domain-
dc.subject.meshCrystallography, X-Ray-
dc.subject.meshDrug Design-
dc.subject.meshHumans-
dc.subject.meshKinetics-
dc.subject.meshModels, Chemical-
dc.subject.meshProtein Binding-
dc.subject.meshQuinone Reductases-
dc.subject.meshQuinones-
dc.subject.meshRecombinant Proteins-
dc.titleStructure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones.en
dc.typeArticleen
dc.contributor.departmentDepartment of Biophysics and Biophysical Chemistry, Johns Hopkins Medical School, Baltimore, MD 21205, USA.en
dc.identifier.journalStructureen

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