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

Recent research has identified that adenosine A_2A receptor (A_2AR) antagonists are promising agents for Cancer Immunotherapy. However, their limited efficacy as monotherapies remains an unresolved challenge. A_2AR/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 (A_2AR K_i = 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.