2. Academic Validation
  3. Asymmetrically Substituted Quadruplex-Binding Naphthalene Diimide Showing Potent Activity in Pancreatic Cancer Models

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

  • ACS Med Chem Lett. 2020 Jul 16;11(8):1634-1644. doi: 10.1021/acsmedchemlett.0c00317.
Ahmed A Ahmed 1,  Richard Angell 1,  Sally Oxenford 1,  Jenny Worthington 2,  Nicole Williams 2,  Naomi Barton 3,  Thomas G Fowler 3,  Daniel E O'Flynn 3,  Mihiro Sunose 3,  Matthew McConville 3,  Tam Vo 4,  W David Wilson 4,  Saadia A Karim 5,  Jennifer P Morton 5 6,  Stephen Neidle 1
Affiliations

Affiliations

  • 1 School of Pharmacy, University College London, London WC1N 1AX, United Kingdom.
  • 2 Axis Bio Discovery Services, Ltd., Coleraine, Northern Ireland BT51 3RP, United Kingdom.
  • 3 Sygnature Discovery Limited, Nottingham NG1 1GR, United Kingdom.
  • 4 Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, Georgia 30303-3083, United States.
  • 5 Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom.
  • 6 Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom.
PMID: 32832034 DOI: 10.1021/acsmedchemlett.0c00317
Abstract

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.

Figures
Products