Medicinal Chemistry Strategies for the Development of CD73 Inhibitors in Cancer Immunotherapy.

CD73, a membrane-bound ecto-5'-nucleotidase, catalyzes the extracellular conversion of adenosine monophosphate into immunosuppressive adenosine. Functioning as an emerging immune checkpoint, CD73 is frequently upregulated across numerous tumor types, contributing to the accumulation of adenosine within the tumor microenvironment and promoting immune evasion. Intensive efforts have led to the discovery of diverse CD73 inhibitors, which show strong potential in cancer immunotherapy. To date, around eighteen candidates targeting CD73 have entered clinical evaluation, many exhibiting encouraging efficacy in combination regimens for solid tumors. This review provides an overview of the biological functions of CD73 in tumor-induced immunosuppression and highlights the medicinal chemistry strategies employed in the development of small-molecule CD73 inhibitors since 2018. Additionally, the challenges in drug design and future directions are also discussed to enhance the clinical applicability of CD73-targeted therapies in cancer treatment. We believe that this review will offer valuable insights to guide the rational design of next-generation CD73 inhibitors for cancer immunotherapy.