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Novel DNA Bis-Intercalator XR5944 as a Potent Anticancer Drug-Design and Mechanism of Action.

ABSTRACT: This review is dedicated to Professor William A. Denny's discovery of XR5944 (also known as MLN944). XR5944 is a DNA-targeted agent with exceptionally potent antitumor activity and a novel DNA binding mode, bis-intercalation and major groove binding, as well as a novel mechanism of action, transcription inhibition. This novel anticancer compound represents a remarkable accomplishment resulting from two decades of drug discovery by Professor Denny and coworkers. Here, we review our work on the structural study of the DNA binding mode of XR5944 and mechanistic study of XR5944 action.

SUBMITTER: Buric AJ

PROVIDER: S-EPMC8304338 | biostudies-literature |

REPOSITORIES: biostudies-literature

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DNA Recognition by a Novel Bis-Intercalator, Potent Anticancer Drug XR5944.

Project description:XR5944 is a potent anticancer drug with a novel DNA binding mode: DNA bisintercalationg with major groove binding. XR5944 can bind the estrogen response element (ERE) sequence to block ER-ERE binding and inhibit ER? activities, which may be useful for overcoming drug resistance to currently available antiestrogen treatments. This review discusses the progress relating to the structure and function studies of specific DNA recognition of XR5944. The sites of intercalation within a native promoter sequence appear to be different from the ideal binding site and are context- and sequence- dependent. The structural information may provide insights for rational design of improved EREspecific XR5944 derivatives, as well as of DNA bis-intercalators in general.

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Solution structure of a 2:1 complex of anticancer drug XR5944 with TFF1 estrogen response element: insights into DNA recognition by a bis-intercalator.

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Probing the Mechanism of Action of Bis(phenolato) Amine (ONO Donor Set) Titanium(IV) Anticancer Agents.

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The Anticancer Mechanism of the Ribonucleotide Reductase Inhibiting Drug COH29 Involves Suppression of DNA Repair

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