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Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC.
J Am Chem Soc 2019; 141(28):11059-11070JA

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.

Authors+Show Affiliations

Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy , Purdue University , 575 W Stadium Avenue , West Lafayette , Indiana 47907 , United States.Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy , Purdue University , 575 W Stadium Avenue , West Lafayette , Indiana 47907 , United States.Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy , Purdue University , 575 W Stadium Avenue , West Lafayette , Indiana 47907 , United States.Department of Chemistry and Physical Sciences , Pace University , 1 Pace Plaza , New York , New York 10038 , United States.Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy , Purdue University , 575 W Stadium Avenue , West Lafayette , Indiana 47907 , United States. Purdue Center for Cancer Research , 201 S University Street , West Lafayette , Indiana 47906 , United States. Purdue Institute for Drug Discovery , 720 Clinic Drive , West Lafayette , Indiana 47907 , United States.Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy , Purdue University , 575 W Stadium Avenue , West Lafayette , Indiana 47907 , United States. Purdue Center for Cancer Research , 201 S University Street , West Lafayette , Indiana 47906 , United States. Purdue Institute for Drug Discovery , 720 Clinic Drive , West Lafayette , Indiana 47907 , United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31283877

Citation

Wang, Kai-Bo, et al. "Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC." Journal of the American Chemical Society, vol. 141, no. 28, 2019, pp. 11059-11070.
Wang KB, Elsayed MSA, Wu G, et al. Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC. J Am Chem Soc. 2019;141(28):11059-11070.
Wang, K. B., Elsayed, M. S. A., Wu, G., Deng, N., Cushman, M., & Yang, D. (2019). Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC. Journal of the American Chemical Society, 141(28), pp. 11059-11070. doi:10.1021/jacs.9b02679.
Wang KB, et al. Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC. J Am Chem Soc. 2019 Jul 17;141(28):11059-11070. PubMed PMID: 31283877.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC. AU - Wang,Kai-Bo, AU - Elsayed,Mohamed S A, AU - Wu,Guanhui, AU - Deng,Nanjie, AU - Cushman,Mark, AU - Yang,Danzhou, Y1 - 2019/07/08/ PY - 2019/7/10/pubmed PY - 2019/7/10/medline PY - 2019/7/9/entrez SP - 11059 EP - 11070 JF - Journal of the American Chemical Society JO - J. Am. Chem. Soc. VL - 141 IS - 28 N2 - 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. SN - 1520-5126 UR - https://www.unboundmedicine.com/medline/citation/31283877/Indenoisoquinoline_Topoisomerase_Inhibitors_Strongly_Bind_and_Stabilize_the_MYC_Promoter_G-Quadruplex_and_Downregulate_MYC L2 - https://dx.doi.org/10.1021/jacs.9b02679 DB - PRIME DP - Unbound Medicine ER -