2. Academic Validation
  3. Discovery of Novel d-(+)-Biotin-Conjugated Resorcinol Dibenzyl Ether-Based PD-L1 Inhibitors for Targeted Cancer Immunotherapy

Discovery of Novel d-(+)-Biotin-Conjugated Resorcinol Dibenzyl Ether-Based PD-L1 Inhibitors for Targeted Cancer Immunotherapy

  • J Med Chem. 2023 Aug 10;66(15):10364-10380. doi: 10.1021/acs.jmedchem.3c00479.
Zongbao Ding 1,  Shuanghu Wang 2,  Yaru Shi 2,  Xiaoting Fei 3,  Binbin Cheng 3,  Yiyu Lu 4,  Jianjun Chen 5
Affiliations

Affiliations

  • 1 Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, P. R. China.
  • 2 The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui, Lishui, Zhejiang 323000, China.
  • 3 School of Medicine, Hubei Polytechnic University, Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Huangshi 435003, China.
  • 4 Oncology Department, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan 528200, China.
  • 5 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
PMID: 37480153 DOI: 10.1021/acs.jmedchem.3c00479
Abstract

In this work, we rationally designed, synthesized, and evaluated a series of novel d-(+)-biotin-conjugated PD-L1 inhibitors for targeted Cancer therapy. Among them, SWS1 exhibited the highest anti-PD-1/PD-L1 activity with an IC50 of 1.8 nM. In addition, SWS1 dose-dependently promoted tumor cell death in a HepG2/Jurkat cell co-culture model. Importantly, SWS1 displayed high antitumor efficacy in a B16-F10 mouse model with tumor growth inhibition of 66.1%, which was better than that of P18 (44.3%). Furthermore, SWS1 exerted antitumor effects by increasing the number of tumor-infiltrating lymphocytes and reducing the expression of PD-L1 in tumor tissues. Moreover, tissue distribution studies revealed a substantial accumulation of SWS1 in tumors (404.1 ng/mL). Lastly, the safety profiles of SWS1 were better (e.g., less immune-mediated colitis) than those of P18, indicating the advantages of biotin-enabled tumor targeting capability. Taken together, our results suggest that these novel tumor-targeted PD-L1 inhibitors are worthy of further investigation as potential Anticancer agents for targeted Cancer Immunotherapy.

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