Discovery of Small and Bifunctional Molecules Targeting PD-L1/CD73 for Cancer Dual Immunotherapy

  • J Med Chem. 2024 Jun 13;67(11):9447-9464. doi: 10.1021/acs.jmedchem.4c00553.
Shuanghu Wang  1  2 ,  Zhihua Kong  3 ,  Yaru Shi  1 ,  Chuxiao Shao  1 ,  Wei Wang  4 ,  Zhenhong Su  5 ,  Jin Liu  5 ,  Yingxing Zhou  5 ,  Xiaoting Fei  5 ,  Binbin Cheng  1  2  5 ,  Jianjun Chen  6 ,  Yiyu Lu  7 ,  Jian Xiao  2
Affiliations
  • 1. Central Laboratory, Wenzhou Medical University Lishui Hospital, Lishui People's Hospital, Lishui, Zhejiang 323000, China.
  • 2. Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325035, China.
  • 3. Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou 528200, China.
  • 4. Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
  • 5. Hubei Key Laboratory of Renal Disease Occurrence and Intervention, Department of Pharmacy, School of Medicine, Hubei Polytechnic University, Huangshi, Hubei 435003, China.
  • 6. School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
  • 7. Oncology Department, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan 528200, China.
PMID: 38748913 DOI: 10.1021/acs.jmedchem.4c00553
Abstract

In this work, a series of bifunctional PD-L1/CD73 (cluster of differentiation 73) small-molecule inhibitors were designed and synthesized. Among them, CC-5 showed the strongest PD-L1 inhibitory effects with an IC50 of 6 nM and potent anti-CD73 activity with an IC50 of 0.773 μM. The high PD-L1/CD73 inhibitory activity of CC-5 was further confirmed by SPR assays with KD of 182 nM for human PD-L1 and 101 nM for CD73, respectively. Importantly, CC-5 significantly suppressed tumor growth in a CT26 and B16-F10 tumor model with TGI of 64.3% and 39.6%, respectively. Immunohistochemical (IHC) and flow cytometry analysis of tumor-infiltrating lymphocytes (TILs) indicated that CC-5 exerted Anticancer effects via activating the tumor immune microenvironment. Collectively, CC-5 represents the first dual PD-L1/CD73 Inhibitor worthy of further research as a bifunctional immunotherapeutic agent.

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