2. Academic Validation
  3. Discovery of Small and Bifunctional Molecules Targeting PD-L1/CD73 for Cancer Dual Immunotherapy

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

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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