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

Danzhou Yang,Adam J Buric,Jonathan Dickerhoff

doi:10.3390/molecules26144132

Danzhou Yang, Adam J Buric + Show 1 more

Open Access

https://doi.org/10.3390/molecules26144132

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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.

Highlights

Despite tremendous advances in cancer therapeutics in recent decades, there is an obvious and urgent need for more effective anticancer drugs
Our study shows that XR5944 bisintercalates dsDNA, with its diamine linker positioned in the major groove, and inhibits the DNA binding of transcription factor estrogen receptor (ER) to the estrogen response element (ERE) in gene promoters
We examined the effect of different trinucleotide spacers on XR5944 binding to the consensus ERE sequence in vitro [30]

Summary

Introduction

Despite tremendous advances in cancer therapeutics in recent decades, there is an obvious and urgent need for more effective anticancer drugs. XR5944 ( known as MLN944), bis(9-methylphenazine-1-carboxamide) (Figure 1A) is an exceptionally potent antitumor agent with a novel DNA binding mode and mechanism of action, namely dsDNA bis-intercalation with major groove binding and transcription inhibition [4,5,6]. It displays exceptional cytotoxic potency against a wide range of human cancer cell lines, including leukemia and solid tumors such as colon, small cell lung carcinoma (SCLC), and non-small cell lung carcinoma, with in vitro EC50 in the range. Complex with duplex DNA provide molecular-level details of its DNA binding mode and insights into its mechanism of action of transcriptional inhibition

XR5944

Effect

Solution

Disrupting ERE-ERα Complex Formation: A Potential Alternative to