Catechols and 3-hydroxypyridones as inhibitors of the DNA repair complex ERCC1-XPF

Bioorganic & Medicinal Chemistry Letters
Timothy M ChapmanBarbara Saxty

Abstract

Catechol-based inhibitors of ERCC1-XPF endonuclease activity were identified from a high-throughput screen. Exploration of the structure-activity relationships within this series yielded compound 13, which displayed an ERCC1-XPF IC50 of 0.6 μM, high selectivity against FEN-1 and DNase I and activity in nucleotide excision repair, cisplatin enhancement and γH2AX assays in A375 melanoma cells. Screening of fragments as potential alternatives to the catechol group revealed that 3-hydroxypyridones are able to inhibit ERCC1-XPF with high ligand efficiency, and elaboration of the hit gave compounds 36 and 37 which showed promising ERCC1-XPF IC50 values of <10 μM.

References

Sep 26, 2014·Nature·Jonathan Baell, Michael A Walters

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Citations

Feb 21, 2016·Pharmacology & Therapeutics·Navnath S GavandeJohn J Turchi
Sep 1, 2015·Bioorganic & Medicinal Chemistry Letters·Timothy M ChapmanBarbara Saxty
Jan 1, 2020·Chemical Biology & Drug Design·Francesco GentileJack A Tuszynski
May 7, 2020·International Journal of Molecular Sciences·Karol BukowskiRenata Kontek
Apr 9, 2020·Frontiers in Pharmacology·Jiabei ZhouLushan Yu
Apr 30, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Daniel P FeldmannOlivia M Merkel
Jan 6, 2021·Cancer Chemotherapy and Pharmacology·Gloria CinieroLars Petter Jordheim
Oct 8, 2020·Journal of Medicinal Chemistry·Xiaoying JiangYuanyuan Xie
Aug 2, 2019·Journal of Medicinal Chemistry·Ahmed H ElmenoufyFrederick G West
Aug 31, 2021·RSC Chemical Biology·Kerry Silva McPherson, Dmitry M Korzhnev

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