2. Academic Validation
  3. Discovery of novel 7,8-dihydropteridine-6(5H)-one-based DNA-PK inhibitors as potential anticancer agents via scaffold hopping strategy

Discovery of novel 7,8-dihydropteridine-6(5H)-one-based DNA-PK inhibitors as potential anticancer agents via scaffold hopping strategy

  • Eur J Med Chem. 2022 Jul 5;237:114401. doi: 10.1016/j.ejmech.2022.114401.
Zongbao Ding 1,  Wei Pan 2,  Yao Xiao 3,  Binbin Cheng 4,  Gang Huang 5,  Jianjun Chen 6
Affiliations

Affiliations

  • 1 Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519041, PR China.
  • 2 Department of Cardiology, The Sixth Affiliated Hospital, South China University of Technology, Nanhai People's Hospital, Foshan, Guangdong, 528200, PR China.
  • 3 Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan Wuchang Hospital, Wuchang, 430063, PR China.
  • 4 School of Medicine, Hubei Polytechnic University, Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Huangshi, 435003, PR China. Electronic address: 2248549496@qq.com.
  • 5 Department of Hematology, Yuebei People's Hospital, Shantou University Medical College, Shaoguan, Guangdong, 51200, PR China. Electronic address: huanggangxy@163.com.
  • 6 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, PR China; Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China. Electronic address: jchen21@smu.edu.cn.
PMID: 35468512 DOI: 10.1016/j.ejmech.2022.114401
Abstract

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 γH2A.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.

Keywords

Anticancer agents; DNA-PK Inhibitors; Scaffold hopping.

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