Identification and validation of novel SULT2B1b inhibitors

Since the initial approval of anti-CTLA4 therapy for the treatment of melanoma in 2011, immune checkpoint blockade (ICB) immunotherapy has become widely regarded as one of the most promising advances made in cancer treatment in recent years. However, across cancer types, response rates to ICB are low owing to other immunosuppressive mechanisms that cancers employ to evade the immune system. One such mechanism is the production of immunosuppressive metabolites that can affect the tumor microenvironment and generate a localized immunosuppressive environment. In these cases, immune cell function is decreased and cannot be restored until the immunosuppressive microenvironment is disrupted. It is thought that disruption of the immunosuppressive microenvironment would restore immune cell function, and this strategy could be further combined with ICB to increase response rates. Small molecule inhibitors of some immunosuppressive metabolite-generating enzymes are currently being investigated in clinical trials, supporting the validity of this approach. Cholesterol sulfate (CS) has recently been identified as an immunosuppressive metabolite that has deleterious effects on T cell motility and activation. Elevated levels have been reported in cancerous tissues, suggesting this as a potential mechanism that is used to generate an immunosuppressive tumor microenvironment. Herein, we report small molecule inhibitors of SULT2B1b. Using a series of biochemical and whole cell in vitro experiments and screening of complex-and-diverse compounds, we now report the discovery of compounds that inhibit SULT2B1b in vitro and inhibit CS production in cancer cells. These compounds are important chemical probes for validating SULT2B1b as a target for enhancing antitumor immunity and can be used to further understand the interplay between CS and the immune system.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Chatkewitz, Lindsay Elizabeth

Contributors dc:contributor

• Hergenrother, Paul J
• Fan, Timothy M
• Zimmerman, Steven C
• Mehta, Angad P

• SULT2B1b
• cholesterol sulfotransferase
• cholesterol sulfate

Statement dc:rights

• Copyright 2022 Lindsay Chatkewitz

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/115679

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F115679