CD73 Inhibitors as Antitumor Agents

5′-Ectonucleotidase (e5NT), a metalloenzyme incorporating two zinc ions in its structure, also known as CD73, hydrolyzes AMP to phosphate and adenosine. It is involved in several physiological and pathological processes, among which immune homeostasis, inflammation, tumor progression. The last decade saw the development of small molecule and monoclonal antibodies (MAbs) acting as CD73 inhibitors in the search of novel immunotherapeutic agents for the management of many tumor types. CD73 X-ray crystal structure, alone as well as in complex with a non-hydrolyzable adenosine diphosphate (ADP) analog, adenosine (α,β)-methylene diphosphate (AMPCP), but also with other types of inhibitors, has been reported. This has been useful for the design of effective nucleotide/nucleoside-based CD73 inhibitors. Medicinal chemistry campaigns based on the identified leads thereafter afforded many other such inhibitors. The main strategies for obtaining them included the modifications of the nucleobase, changes at the sugar moiety as well as to zinc-binding groups of the lead compounds. Non-nucleotide CD73 inhibitors were also reported, belonging to the following chemical classes: flavones, anthraquinone sulfonates, primary sulfonamides, etc. One of the most effective in vitro small molecule CD73 inhibitors, known as AB680, is nowadays in clinical trials as an immunotherapeutic, antitumor agent with a new mechanism of action.