Abstract
XR5944, a deoxyribonucleic acid (DNA) bis-intercalator with potent anticancer activity, can bind the estrogen response element (ERE) sequence to inhibit estrogen receptor-α activities. This novel mechanism of action may be useful for overcoming drug resistance to currently available antiestrogen treatments, all of which target the hormone-receptor complex. Here we report the nuclear magnetic resonance solution structure of the 2:1 complex of XR5944 with the naturally occurring TFF1-ERE, which exhibits important and unexpected features. In both drug–DNA complexes, XR5944 binds strongly at one intercalation site but weakly at the second site. The sites of intercalation within a native promoter sequence appear to be context and sequence dependent. The binding of one drug molecule influences the binding site of the second. Our structures underscore the fact that the DNA binding of a bis-intercalator is directional and different from the simple addition of two single intercalation sites. Our study suggests that improved XR5944 bis-intercalators targeting ERE may be designed through optimization of aminoalkyl linker and intercalation moieties at the weak binding sites.
Highlights
Breast cancer is the most commonly occurring cancer in women and it remains a leading cause of cancer deaths in women despite major advances in treatment over the past 20 years
We previously showed that XR5944, a deoxyribonucleic acid (DNA) bisintercalator with potent anticancer activity, is capable of inhibiting ER␣-mediated transcriptional responses via its ability to block the binding of ER␣ to the estrogen response element (ERE) sequence [10]
We have previously shown that XR5944, a DNA bisintercalator with potent anticancer activity, is capable of inhibiting ER␣-mediated transcriptional responses via its ability to block the binding of ER␣ to the ERE sequence [10]
Summary
Breast cancer is the most commonly occurring cancer in women and it remains a leading cause of cancer deaths in women despite major advances in treatment over the past 20 years. ER␣ regulates transcription of target genes through direct binding to its cognate recognition sites, known as estrogen response elements (EREs), or by modulating the activity of other deoxyribonucleic acid (DNA) binding transcription factors at alternative DNA sequences [3]. ER␣ modulation by endocrine therapy is the primary means to treat ER␣-positive breast tumors [4]. These antiestrogen treatments are comprised of selective ER modulators (e.g. tamoxifen), which impair the hormone-receptor complex [5], and aromatase inhibitors (AIs, e.g. anastrazole), which inhibit E2 production [6,7]. A significant fraction (∼20–50%) of ER␣-positive breast tumors fail to respond [8] or eventually develop resistance to antiestrogen treatments [9]. There remains an urgent need for new and effective agents that overcome the resistance to existing endocrine therapies
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