Pharmacokinetics-Driven Optimization of Immunotherapeutic Agents Targeting the Adenosine A2A Receptor (A2AR) and Histone Deacetylases (HDACs)

Recent research has identified that adenosine A2A receptor (A2AR) antagonists are promising agents for cancer immunotherapy. However, their limited efficacy as monotherapies remains an unresolved challenge. A2AR/HDAC dual-targeting compounds have demonstrated more potent antitumor efficacy and warrant further investigation. To further improve the drug-like properties of such compounds in our previous work, a pharmacokinetics-driven structural optimization campaign was undertaken and led to the identification of compound 13t (IHCH-3185), which exhibited a markedly enhanced pharmacokinetic profile in mice. Furthermore, 13t retained potent target engagement (A2AR Ki = 7.6 nM, HDAC1 IC50 = 102.9 nM) and demonstrated broad-spectrum antiproliferative activity in vitro. Oral administration of 13t significantly inhibited CT26 and MC38 tumor growth in mice with tumor growth inhibition rates of 68.5% and 71.1%, respectively. This robust activity was attributed to a dual mechanism combining immune stimulation and direct antiproliferative effects. These results make 13t a promising cancer immunotherapy drug candidate.