1. Academic Validation
  2. Discovery of Novel Benzo[4,5]imidazo[1,2- a]pyrazin-1-amine-3-amide-one Derivatives as Anticancer Human A2A Adenosine Receptor Antagonists

Discovery of Novel Benzo[4,5]imidazo[1,2- a]pyrazin-1-amine-3-amide-one Derivatives as Anticancer Human A2A Adenosine Receptor Antagonists

  • J Med Chem. 2022 Jul 14;65(13):8933-8947. doi: 10.1021/acs.jmedchem.2c00101.
Shuhao Liu 1 Wen Ding 1 Weifeng Huang 1 Zhijing Zhang 1 Yinfeng Guo 1 Qiyi Zhang 1 2 Linna Wu 1 Yukai Li 1 Rui Qin 1 Jiahao Li 1 Taoda Shi 1 Xiaolei Zhang 1 2 Jinping Lei 1 Wenhao Hu 1
Affiliations

Affiliations

  • 1 Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China.
  • 2 National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China.
Abstract

The blockade of A2A Adenosine Receptor (A2AAR) activates immunostimulatory response through regulating signaling in tumor microenvironment. Thus, A2AAR has been proposed as a promising target for Cancer Immunotherapy. In this work, we designed a new series of benzo[4,5]imidazo[1,2-a]pyrazin-1-amine derivatives bearing an amide substitution at 3-position to obtain potent antitumor antagonist in vivo. The structure-activity relationship studies were performed by molecular modeling and radioactive assay. The in vitro Anticancer activities were evaluated by 3',5'-cyclic adenosine monophosphate (cAMP) functional and T cell activation assay. The most potent compound 12o·2HCl showed much higher affinity toward A2AAR (Ki = 0.08 nM) and exhibited more significant in vitro immunostimulatory Anticancer activity than clinical antagonist AZD4635. More importantly, 12o·2HCl significantly inhibited the growth of triple-negative breast Cancer by reversing immunosuppressive tumor microenvironment in the xenograft mouse model without severe toxicity at the testing dose. These results make 12o·2HCl a promising immunotherapy Anticancer drug candidate.

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