Mechanistic Investigation of Site-specific DNA Methylating Agents Targeting Breast Cancer Cells

We previously described the development of a DNA-alkylating compound that showed selective toxicity in breast cancer cells. This compound contained an estrogen receptor α (ERα)-binding ligand and a DNA-binding/methylating component that could selectively methylate the N3-position of adenines at aden...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of medicinal chemistry 2021-09, Vol.64 (17), p.12651-12669
Hauptverfasser: Lowder, Leah L, Powell, Matthew, Miller, Sean E, Kishton, Rigel J, Kelly, Charles B, Cribb, Connor B, Mastro-Kishton, Kelly, Chelvanambi, Manoj, Do, Phat T, Govindapur, Rajeshwar Reddy, Wardell, Suzanne E, McDonnell, Donald P, Bartolotti, Libero J, Akkaraju, Giridhar R, Frampton, Arthur R, Varadarajan, Sridhar
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:We previously described the development of a DNA-alkylating compound that showed selective toxicity in breast cancer cells. This compound contained an estrogen receptor α (ERα)-binding ligand and a DNA-binding/methylating component that could selectively methylate the N3-position of adenines at adenine–thymine rich regions of DNA. Herein, we describe mechanistic investigations that demonstrate that this class of compounds facilitate the translocation of the ERα-compound complex to the nucleus and induce the expression of ERα target genes. We confirm that the compounds show selective toxicity in ERα-expressing cells, induce ERα localization in the nucleus, and verify the essential role of ERα in modulating the toxicity. Minor alterations in the compound structure significantly affects the DNA binding ability, which correlates to the DNA-methylating ability. These studies demonstrate the utility of DNA-alkylating compounds to accomplish targeted inhibition of the growth of specific cancer cells; an approach that may overcome shortcomings of currently used chemotherapy agents.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c00615