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Article Abstract
Adenosine is an immunosuppressive factor in the tumor microenvironment mainly through activation of the A adenosine receptor (AR), which is a mechanism hijacked by tumors to escape immune surveillance. Small-molecule AR antagonists are being evaluated in clinical trials as immunotherapeutic agents, but their efficacy is limited as standalone therapies. To enhance the antitumor effects of AR antagonists, dual-acting compounds incorporating AR antagonism and histone deacetylase (HDAC) inhibitory actions were designed and synthesized, based on co-crystal structures of AR. Compound (IHCH-3064) exhibited potent binding to AR ( = 2.2 nM) and selective inhibition of HDAC1 (IC = 80.2 nM), with good antiproliferative activity against tumor cell lines in vitro. Intraperitoneal administration of (60 mg/kg, bid) inhibited mouse MC38 tumor growth with a tumor growth inhibition rate of 95.3%. These results showed that dual-acting compounds targeting AR and HDAC are potentially immunotherapeutic agents that are worth further exploring.
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| http://dx.doi.org/10.1021/acs.jmedchem.1c01155 | DOI Listing |
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