Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC

Kai Bo Wang, Mohamed S.A. Elsayed, Guanhui Wu, Nanjie Deng, Mark Cushman, Danzhou Yang

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

MYC is one of the most important oncogenes and is overexpressed in the majority of cancers. G-Quadruplexes are noncanonical four-stranded DNA secondary structures that have emerged as attractive cancer-specific molecular targets for drug development. The G-quadruplex formed in the proximal promoter region of the MYC oncogene (MycG4) has been shown to be a transcriptional silencer that is amenable to small-molecule targeting for MYC suppression. Indenoisoquinolines are human topoisomerase I inhibitors in clinical testing with improved physicochemical and biological properties as compared to the clinically used camptothecin anticancer drugs topotecan and irinotecan. However, some indenoisoquinolines with potent anticancer activity do not exhibit strong topoisomerase I inhibition, suggesting a separate mechanism of action. Here, we report that anticancer indenoisoquinolines strongly bind and stabilize MycG4 and lower MYC expression levels in cancer cells, using various biochemical, biophysical, computer modeling, and cell-based methods. Significantly, a large number of active indenoisoquinolines cause strong MYC downregulation in cancer cells. Structure-activity relationships of MycG4 recognition by indenoisoquinolines are investigated. In addition, the analysis of indenoisoquinoline analogues for their MYC-inhibitory activity, topoisomerase I-inhibitory activity, and anticancer activity reveals a synergistic effect of MYC inhibition and topoisomerase I inhibition on anticancer activity. Therefore, this study uncovers a novel mechanism of action of indenoisoquinolines as a new family of drugs targeting the MYC promoter G-quadruplex for MYC suppression. Furthermore, the study suggests that dual targeting of MYC and topoisomerase I may serve as a novel strategy for anticancer drug development.

Original languageEnglish (US)
Pages (from-to)11059-11070
Number of pages12
JournalJournal of the American Chemical Society
Volume141
Issue number28
DOIs
StatePublished - Jul 17 2019

Fingerprint

Topoisomerase Inhibitors
G-Quadruplexes
Type I DNA Topoisomerase
Down-Regulation
Cells
irinotecan
Oncogenes
Neoplasms
DNA
Pharmaceutical Preparations
Topoisomerase I Inhibitors
Topotecan
Camptothecin
Molecules
Testing
Drug Delivery Systems
Structure-Activity Relationship
Genetic Promoter Regions

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC. / Wang, Kai Bo; Elsayed, Mohamed S.A.; Wu, Guanhui; Deng, Nanjie; Cushman, Mark; Yang, Danzhou.

In: Journal of the American Chemical Society, Vol. 141, No. 28, 17.07.2019, p. 11059-11070.

Research output: Contribution to journalArticle

Wang, Kai Bo ; Elsayed, Mohamed S.A. ; Wu, Guanhui ; Deng, Nanjie ; Cushman, Mark ; Yang, Danzhou. / Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC. In: Journal of the American Chemical Society. 2019 ; Vol. 141, No. 28. pp. 11059-11070.
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AU - Elsayed, Mohamed S.A.

AU - Wu, Guanhui

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AU - Cushman, Mark

AU - Yang, Danzhou

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AB - MYC is one of the most important oncogenes and is overexpressed in the majority of cancers. G-Quadruplexes are noncanonical four-stranded DNA secondary structures that have emerged as attractive cancer-specific molecular targets for drug development. The G-quadruplex formed in the proximal promoter region of the MYC oncogene (MycG4) has been shown to be a transcriptional silencer that is amenable to small-molecule targeting for MYC suppression. Indenoisoquinolines are human topoisomerase I inhibitors in clinical testing with improved physicochemical and biological properties as compared to the clinically used camptothecin anticancer drugs topotecan and irinotecan. However, some indenoisoquinolines with potent anticancer activity do not exhibit strong topoisomerase I inhibition, suggesting a separate mechanism of action. Here, we report that anticancer indenoisoquinolines strongly bind and stabilize MycG4 and lower MYC expression levels in cancer cells, using various biochemical, biophysical, computer modeling, and cell-based methods. Significantly, a large number of active indenoisoquinolines cause strong MYC downregulation in cancer cells. Structure-activity relationships of MycG4 recognition by indenoisoquinolines are investigated. In addition, the analysis of indenoisoquinoline analogues for their MYC-inhibitory activity, topoisomerase I-inhibitory activity, and anticancer activity reveals a synergistic effect of MYC inhibition and topoisomerase I inhibition on anticancer activity. Therefore, this study uncovers a novel mechanism of action of indenoisoquinolines as a new family of drugs targeting the MYC promoter G-quadruplex for MYC suppression. Furthermore, the study suggests that dual targeting of MYC and topoisomerase I may serve as a novel strategy for anticancer drug development.

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