Citation: Ruiquan Liu, Wenwen Duan, Wenzhong Yan, Jinfeng Zhang, Jianjun Cheng. Design and synthesis of tri-substituted pyrimidine derivatives as bifunctional tumor immunotherapeutic agents targeting both A_2A adenosine receptors and histone deacetylases[J]. Chinese Chemical Letters, ;2024, 35(1): 108136. doi: 10.1016/j.cclet.2023.108136 shu

Design and synthesis of tri-substituted pyrimidine derivatives as bifunctional tumor immunotherapeutic agents targeting both A_2A adenosine receptors and histone deacetylases

Ruiquan Liu ^a ,
Wenwen Duan ^a ,
Wenzhong Yan ^a ,
Jinfeng Zhang ^a ,
Jianjun Cheng ^{a, b, *,}

a.
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
b.
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China

chengjj@shanghaitech.edu.cn

Received Date: 11 October 2022
Revised Date: 3 January 2023
Accepted Date: 4 January 2023
Available Online: 5 January 2023

Figures(5)

The A_2A adenosine receptor (A_2AAR) has attracted attention as an emerging immunotherapeutic target with several antagonists being evaluated in clinical trials. However, A_2AAR antagonists show limited efficacy as monotherapies. Herein, we communicate our design and synthesis of a novel series of A_2AAR/histone deacetylase (HDAC) bifunctional inhibitors, based on the core structure of the A_2AAR antagonist PBF-509. The new compounds were designed using a pharmacophore-merging strategy and features a tri-substituted pyrimidine core. The binding affinity for A_2AAR and inhibitory activity against HDACs of all the new compounds were tested. A number of compounds exhibited nanomolar or subnanomolar activity against both targets and some showed equally potent antiproliferative activity against MC38, CT26 and HCT116 colon cancer lines compared to HDAC inhibitors SAHA and MGCD-0103 in vitro. The binding poses of compound 5a in both A_2AAR and HDAC1 were predicted by molecular docking studies. Collectively, these results suggest these tri-substituted pyrimidine derivatives are promising leads for developing A_2AAR/HDAC dual-acting compounds as novel antitumor agents.
- Bifunctional,
- A_2AAR antagonism,
- HDAC inhibition,
- Cancer,
- Immunotherapy
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Design and synthesis of tri-substituted pyrimidine derivatives as bifunctional tumor immunotherapeutic agents targeting both A2A adenosine receptors and histone deacetylases

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通讯作者: 陈斌, bchen63@163.com

Design and synthesis of tri-substituted pyrimidine derivatives as bifunctional tumor immunotherapeutic agents targeting both A_2A adenosine receptors and histone deacetylases