2. Academic Validation
  3. Discovery of Novel Heterotricyclic Compounds as DNA-Dependent Protein Kinase (DNA-PK) Inhibitors with Enhanced Chemosensitivity, Oral Bioavailability, and the Ability to Potentiate Cancer Immunotherapy

Discovery of Novel Heterotricyclic Compounds as DNA-Dependent Protein Kinase (DNA-PK) Inhibitors with Enhanced Chemosensitivity, Oral Bioavailability, and the Ability to Potentiate Cancer Immunotherapy

  • J Med Chem. 2024 Apr 25;67(8):6253-6267. doi: 10.1021/acs.jmedchem.3c02231.
Binbin Cheng 1 2 3,  Yaru Shi 1,  Chuxiao Shao 1,  Shuanghu Wang 1,  Zhenhong Su 2,  Jin Liu 2,  Yingxing Zhou 2,  Xiaoting Fei 2,  Wei Pan 4,  Jianjun Chen 5,  Yiyu Lu 6,  Jian Xiao 3
Affiliations

Affiliations

  • 1 Key Laboratory of Joint Diagnosis and Treatment of Chronic Liver Disease and Liver Cancer of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui People's Hospital, Lishui, Zhejiang 323000, China.
  • 2 Hubei Key Laboratory of Renal Disease Occurrence and Intervention, Department of Pharmacy, School of Medicine, Hubei Polytechnic University, Huangshi, Hubei 435003, P. R. China.
  • 3 Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325035, China.
  • 4 Cardiology Department, Geriatric Department, Foshan Women and Children Hospital, Foshan, Guangdong 528000, P. R. China.
  • 5 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, P. R. China.
  • 6 Oncology Department, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan 528200, China.
PMID: 38587857 DOI: 10.1021/acs.jmedchem.3c02231
Abstract

In this work, a novel series of heterotricyclic DNA-PK inhibitors were rationally designed, synthesized, and assessed for their biological activity. In the DNA-PK biochemical assay, most compounds displayed potent enzymatic activity, with IC50 values between 0.11 and 71.5 nM. Among them, SK10 exhibited the most potent DNA-PK-inhibitory activity (IC50 = 0.11 nM). Studies of the mechanism of action indicated that SK10 could lower γH2A.X expression levels and demonstrate optimal synergistic antiproliferative activity against Jurkat cells (IC50 = 25 nM) when combined with doxorubicin. Importantly, in CT26 and B16-F10 tumor-bearing mouse models, the combination therapies of SK10 with chemotherapeutic drug doxorubicin, a PD-L1 antibody, and SWS1 (a potent PD-L1 small-molecule inhibitor) demonstrated superior synergistic Anticancer and potential immunomodulatory effects. Furthermore, SK10 possessed favorable in vivo pharmacokinetic properties [e.g., oral bioavailability (F) = 31.8%]. Taken together, SK10 represents a novel heterotricyclic DNA-PK Inhibitor with antitumor immune effects and favorable pharmacokinetics.

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