Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 237, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114401
Keywords
DNA-PK Inhibitors; Anticancer agents; Scaffold hopping
Categories
Funding
- Wuhan Municipal Health Commission of China [WX21Q48]
- Foshan Outstanding Young Medical Talents Project grants, Foshan Medical Science and Technology Project [2020001004341]
- Hubei Key Laboratory of Kidney Disease Pathogenesis and Intervention [SB202117]
- National Natural Science Foundation of China [82173668]
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DK1 is a novel DNA-PK inhibitor with great potential for further study. It has favorable drug-like properties and in vivo pharmacokinetics as an oral drug candidate. When used in combination with doxorubicin, DK1 shows synergistic antiproliferative activity against various cancer cell lines.
DNA-dependent protein kinase (DNA-PK) is an essential element in the DNA damage response (DDR) pathway and has been regarded as a druggable target for antineoplastic agents. Starting from AZD-7648, a potent DNA-PK inhibitor being investigated in phase II clinical trials for advanced cancer treatment, two series of DNA-PK inhibitors were rationally designed via scaffold hopping strategy, synthesized, and assessed for their biological activity. Most compounds exhibited potent biochemical activity on DNA-PK enzymatic assay with IC50 values below 300 nM. Among these compounds, DK1 showed the best DNA-PK-inhibitory potency (IC50 = 0.8 nM), slightly better than that of AZD-7648 (IC50 = 1.58 nM). Mode of action studies revealed that compound DK1 decreased the expression levels of gamma H2A.X and demonstrated synergistic antiproliferative activity against a series of cancer cell lines when used in combination with doxorubicin. Moreover, DK1 showed reasonable in vitro drug-like properties and favorable in vivo pharmacokinetics as an oral drug candidate. Importantly, the combination therapy of DK1 with DNA double-strand break (DSB)-inducing agent doxorubicin showed synergistic anticancer efficacy in the HL-60 xenograft model with a tumor growth inhibition (TGI) of 52.4% and 62.4% for tumor weight and tumor volume, respectively. In conclusion, DK1 is a novel DNA-PK inhibitor with great promise for further study.
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