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

Abstract

Based on its inhibition by antagonists, the A_2A adenosine receptor (A_2AAR) has attracted attention as an anti-tumor drug target; however, in preclinical models and clinical trials, A_2AAR antagonists have so far shown only limited efficacy as standalone therapies. The design of dual-acting compounds, targeting the A_2AAR 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 A_2AAR 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 A_2AAR of all the new compounds were tested, and their HDAC inhibitory activity was evaluated. Compounds with balanced A_2AAR 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.