Structural investigation on thiazolo[5,4-d]pyrimidines to obtain dual-acting blockers of CD73 and adenosine A2A receptor as potential antitumor agents.

Adenosine pathway, including its generating enzyme (CD73) and its receptors represents a key target for cancer immunotherapy. Here we aimed to search for novel compounds able to co-target the CD73 and the A2A adenosine receptor (A2A AR) as dual-blockers of adenosine generation and activity. The design project was to combine in the same molecule the thiazolo[5,4-d]pyrimidine core, an essential pharmacophoric feature to block the A2A AR, with a benzenesulfonamide group which is a characteristic group of CD73 inhibitors. Most of the reported compounds resulted in inverse agonists of the human (h) A2A AR endowed with high affinity, selectivity and potency. However they were weak inhibitors of CD73 enzyme. Nevertheless, this study can be considered as a starting point to develop more active compounds.