Asymmetrically Substituted Quadruplex-Binding Naphthalene Diimide Showing Potent Activity in Pancreatic Cancer Models.

Autor:	Ahmed AA; School of Pharmacy, University College London, London WC1N 1AX, United Kingdom., Angell R; School of Pharmacy, University College London, London WC1N 1AX, United Kingdom., Oxenford S; School of Pharmacy, University College London, London WC1N 1AX, United Kingdom., Worthington J; Axis Bio Discovery Services, Ltd., Coleraine, Northern Ireland BT51 3RP, United Kingdom., Williams N; Axis Bio Discovery Services, Ltd., Coleraine, Northern Ireland BT51 3RP, United Kingdom., Barton N; Sygnature Discovery Limited, Nottingham NG1 1GR, United Kingdom., Fowler TG; Sygnature Discovery Limited, Nottingham NG1 1GR, United Kingdom., O'Flynn DE; Sygnature Discovery Limited, Nottingham NG1 1GR, United Kingdom., Sunose M; Sygnature Discovery Limited, Nottingham NG1 1GR, United Kingdom., McConville M; Sygnature Discovery Limited, Nottingham NG1 1GR, United Kingdom., Vo T; Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, Georgia 30303-3083, United States., Wilson WD; Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, Georgia 30303-3083, United States., Karim SA; Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom., Morton JP; Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom.; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom., Neidle S; School of Pharmacy, University College London, London WC1N 1AX, United Kingdom.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2020 Jul 16; Vol. 11 (8), pp. 1634-1644. Date of Electronic Publication: 2020 Jul 16 (Print Publication: 2020).
DOI:	10.1021/acsmedchemlett.0c00317
Abstrakt:	Targeting of genomic quadruplexes is an approach to treating complex human cancers. We describe a series of tetra-substituted 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/β-catenin signaling. Competing Interests: The authors declare no competing financial interest. (Copyright © 2020 American Chemical Society.)
Databáze:	MEDLINE
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