ORIC-533 is a potential best-in-class, oral inhibitor of CD73 developed by ORIC Pharmaceuticals which is currently in a Ph. Ib trial for the treatment of relapsed/refractory multiple myeloma (MM). It inhibits the CD73-mediated conversion of AMP to adenosine which generates an immunosuppressive tumor microenvironment and has the potential to be a next-generation immunotherapy. The in-depth use of co-crystal structures led the team to discover a novel set of phosphonate bioisosteres which were able to achieve bioavailability for a highly polar scaffold. The structure and discovery story of ORIC-533 were recently presented at the ACS Spring 2024 Meeting in New Orleans.