2. Academic Validation
  3. Design, synthesis and structure-activity relationship of malonic acid non-nucleoside derivatives as potent CD73 inhibitors

Design, synthesis and structure-activity relationship of malonic acid non-nucleoside derivatives as potent CD73 inhibitors

  • Bioorg Med Chem Lett. 2024 Nov 1:112:129946. doi: 10.1016/j.bmcl.2024.129946.
Cunjian Shi 1,  Jingqi Dai 1,  Longfeng Chang 1,  Wenyue Xu 1,  Chulu Huang 1,  Zhenjiang Zhao 1,  Honglin Li 2,  Lili Zhu 3,  Yufang Xu 4
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 2 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Innovation Center for AI and Drug Discovery, East China Normal University, Shanghai 200062, China; Lingang Laboratory, Shanghai 200031, China.
  • 3 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: zhulfl@ecust.edu.cn.
  • 4 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: yfxu@ecust.edu.cn.
PMID: 39226996 DOI: 10.1016/j.bmcl.2024.129946
Abstract

High levels of extracellular adenosine in tumor microenvironment (TME) has extensive immunosuppressive effect. CD73 catalyzes the conversion of AMP into adenosine and regulates its production. Inhibiting CD73 can reduce the level of adenosine and reverse adenosine-mediated immune suppression. Therefore, CD73 has emerged as a valuable target for Cancer Immunotherapy. Here, a new series of malonic acid non-nucleoside derivatives were designed, synthesized and evaluated as CD73 inhibitors. Among them, compounds 18 and 19 exhibited significant inhibition activities against hCD73 with IC50 values of 0.28 μM and 0.10 μM, respectively, suggesting the feasibility of replacing the benzotriazole moiety in the lead compound. This study explored the novelty and structural diversity of CD73 inhibitors.

Keywords

CD73; Immunotherapy; Non-nucleoside inhibitors.

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