Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 8, Pages 1634-1644Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00317
Keywords
quadruplex; naphthalene diimide derivative; pancreatic cancer; xenograft; transcriptome
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Funding
- Medical Research Council
- Wellcome Trust
- UCL Technology Fund
- CRUK PRECISION-Panc [A25233]
- Cancer Research UK Glasgow Centre [A25142]
- BSU facilities at the Cancer Research UK Beatson Institute (CRUK Experimental Medicine Programme Award) [A25233, A25265]
- Molecular Basis of Disease (MBD) fellowship from the College of Arts and Sciences, Georgia State University
- U.S. National Institutes of Health (NIH) [GM111749]
- MRC [MC_PC_12024] Funding Source: UKRI
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Targeting of genomic quadruplexes is an approach to treating complex human cancers. We describe a series of tetrasubstituted naphthalene diimide (ND) derivatives with a phenyl substituent directly attached to the ND core. The lead compound (SOP1812) has 10 times superior cellular and in vivo activity compared with previous ND compounds and nanomolar binding to human quadruplexes. The pharmacological properties of SOP1812 indicate good bioavailability, which is consistent with the in vivo activity in xenograft and genetic models for pancreatic cancer. Transcriptome analysis shows that it down-regulates several cancer gene pathways, including Wnt/beta-catenin signaling.
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