Small-Molecule Inhibitors of Cholesterol Sulfotransferase as Immunomodulatory Agents
Lindsay E. Boudreau, Amanda J. Smith, Hyang Yeon Lee, Bidisha Chakraborty, Kyle R. Abo, Kenneth Chen, Satish K. Nair, Paul J. HergenrotherAbstract
Though immune checkpoint blockade (ICB) therapy has been a promising advance in cancer treatment, response rates to ICB are low owing to other mechanisms that cancers employ to evade the immune system. SULT2B1b is an enzyme known to produce cholesterol sulfate (CS), an immunosuppressive metabolite that inhibits T-cell migration. Cancers expressing high levels of SULT2B1b thus generate a tumor microenvironment that excludes T cells, which leads to increased tumor growth and renders ICB therapy ineffective. Here, we identify a novel class of azasteroid SULT2B1b inhibitors with greater potency and selectivity than previously identified compounds. X-ray co-crystal structures indicate that these inhibitors bind in a conformation different from that of native substrates, enabling inhibition without acting as a substrate. Additionally, these new compounds effectively reduce CS levels in tumors in mice and, as such, have potential as cancer therapeutics in combination with ICB therapy.