2. Academic Validation
  3. Dual-acting antitumor agents targeting the A2A adenosine receptor and histone deacetylases: Design and synthesis of 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives

Dual-acting antitumor agents targeting the A2A adenosine receptor and histone deacetylases: Design and synthesis of 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives

  • Eur J Med Chem. 2022 Jun 5;236:114326. doi: 10.1016/j.ejmech.2022.114326.
Jinfeng Zhang 1,  Ziwei Luo 2,  Wenwen Duan 3,  Kexin Yang 2,  Lijun Ling 4,  Wenzhong Yan 3,  Ruiquan Liu 3,  Kurt Wüthrich 5,  Hualiang Jiang 6,  Chengying Xie 7,  Jianjun Cheng 8
Affiliations

Affiliations

  • 1 iHuman Institute, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 2 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 3 iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • 4 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.
  • 5 iHuman Institute, ShanghaiTech University, Shanghai, 201210, China; Department of Integrated Structural and Computational Biology, Scripps Research, La Jolla, CA, 92037, USA.
  • 6 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: [email protected].
  • 7 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
  • 8 iHuman Institute, ShanghaiTech University, Shanghai, 201210, China. Electronic address: [email protected].
PMID: 35390714 DOI: 10.1016/j.ejmech.2022.114326
Abstract

Based on its inhibition by antagonists, the A2A Adenosine Receptor (A2AAR) has attracted attention as an anti-tumor drug target; however, in preclinical models and clinical trials, A2AAR antagonists have so far shown only limited efficacy as standalone therapies. The design of dual-acting compounds, targeting the A2AAR and histone deacetylases (HDACs), is used here as an approach to the discovery of novel and more potent antitumor agents. Based on the core structures of the A2AAR antagonists V-2006 and CPI-444, novel 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives were designed as such dual-acting compounds. The binding affinities for A2AAR of all the new compounds were tested, and their HDAC inhibitory activity was evaluated. Compounds with balanced A2AAR antagonism and HDAC inhibition were tested for their in vitro anti-proliferative activity and pharmacokinetic properties. One of the compounds, 14c (4-(2-(6-Amino-4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-N-(2-amino-phenyl)benzamide) showed an overall favorable pharmacokinetic profile; in the mouse MC38 xenograft model, it showed potent anti-tumor effects with inhibition rates of 44% (90 mg/kg, po, bid) and 85% (60 mg/kg, ip, bid), respectively.

Keywords

Bifunctional; Cancer; Immunotherapy; Structure-based.

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