High extracellular concentration of adenosine (Ado) in tumor microenvironment (TME) suppresses all phases of T cell responses to tumors: 1) T cell activation, 2) T cell trafficking, 3) T cell attack on tumor cells. Generation of extracellular Ado in TME depends on the sequential catabolism through two ecto-nucleotidases, CD39 (ATP to AMP) and CD73 (AMP to Ado).  CD39 knock out mice showed multiple toxic phenotypes, whereas, CD73 didn’t show any abnormal physiological symptoms. Furthermore, several animal model studies supported that inhibition of CD73 can inhibit tumor growth. And combination of CD73 inhibition with anti PD-1 antibody displayed synergistic effects. CD73 expression is also associated with poor prognosis in many cancer types. Therefore, inhibition of CD73 may present a whole new approach in cancer immunotherapy. In our efforts to develop CD73 inhibitors, we discovered monophosphonates as CD73 small molecule inhibitors. With further optimization, we discovered SHR170008, a potent small-molecule CD73 inhibitor. Here, we report our discovery and characterization of SHR170008 as a potent small-molecule CD73 inhibitor potentially useful for cancer immunotherapy.<br/>

Discovery and characterization of SHR170008, a potent small-molecule CD73 inhibitor with potential for cancer immunotherapy

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.