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

Shuanghu Wang; Zhihua Kong; Yaru Shi; Chuxiao Shao; Wei Wang; Zhenhong Su; Jin Liu; Yingxing Zhou; Xiaoting Fei; Binbin Cheng; Jianjun Chen; Yiyu Lu; Jian Xiao

doi:10.1021/acs.jmedchem.4c00553

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

J Med Chem. 2024 May 15. doi: 10.1021/acs.jmedchem.4c00553. Online ahead of print.

Authors

Shuanghu Wang^{1

2}, Zhihua Kong³, Yaru Shi¹, Chuxiao Shao¹, Wei Wang⁴, Zhenhong Su⁵, Jin Liu⁵, Yingxing Zhou⁵, Xiaoting Fei⁵, Binbin Cheng^{1

2

5}, Jianjun Chen⁶, Yiyu Lu⁷, Jian Xiao²

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 K_D 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.