Ahmed, A. A. et al. (2020) Asymmetrically substituted quadruplex-binding naphthalene diimide showing potent activity in pancreatic cancer models. ACS Medicinal Chemistry Letters, 11(8), pp. 1634-1644. (doi: 10.1021/acsmedchemlett.0c00317) (PMID:32832034) (PMCID:PMC7429975)
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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.
| Item Type: | Articles |
|---|---|
| Additional Information: | Work in the S.N. laboratory has been supported by the Medical Research Council, the Wellcome Trust, and the UCL Technology Fund. We thank Tony Brooks and the staff of the UCL Genomics Facility for expert assistance with RNA-seq studies at UCL. We are grateful to Professor Daniel Hochhauser (UCL Cancer Institute) for helpful discussions. S.A.K. and J.P.M. acknowledge the support of CRUK PRECISION-Panc (A25233), the Cancer Research UK Glasgow Centre (A25142), and the BSU facilities at the Cancer Research UK Beatson Institute (CRUK Experimental Medicine Programme Award (A25233 and A25265)). T.V. was supported by the Molecular Basis of Disease (MBD) fellowship from the College of Arts and Sciences, Georgia State University. Work in Atlanta was supported by the U.S. National Institutes of Health (NIH) (grant no. GM111749 to W.D.W. and D. W. Boykin). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Morton, Professor Jen and Karim, Ms Saadia |
| Authors: | Ahmed, A. A., Angell, R., Oxenford, S., Worthington, J., Williams, N., Barton, N., Fowler, T. G., O’Flynn, D. E., Sunose, M., McConville, M., Vo, T., Wilson, W. D., Karim, S. A., Morton, J. P., and Neidle, S. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | ACS Medicinal Chemistry Letters |
| Publisher: | American Chemical Society |
| ISSN: | 1948-5875 |
| ISSN (Online): | 1948-5875 |
| Published Online: | 16 July 2020 |
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