Withdraw
Loading…
Identification and validation of novel SULT2B1b inhibitors
Chatkewitz, Lindsay Elizabeth
This item's files can only be accessed by the System Administrators group.
Permalink
https://hdl.handle.net/2142/115679
Description
- Title
- Identification and validation of novel SULT2B1b inhibitors
- Author(s)
- Chatkewitz, Lindsay Elizabeth
- Issue Date
- 2022-04-05
- Director of Research (if dissertation) or Advisor (if thesis)
- Hergenrother, Paul J
- Doctoral Committee Chair(s)
- Hergenrother, Paul J
- Committee Member(s)
- Fan, Timothy M
- Zimmerman, Steven C
- Mehta, Angad P
- Department of Study
- Chemistry
- Discipline
- Chemistry
- Degree Granting Institution
- University of Illinois at Urbana-Champaign
- Degree Name
- Ph.D.
- Degree Level
- Dissertation
- Keyword(s)
- SULT2B1b
- cholesterol sulfotransferase
- cholesterol sulfate
- Abstract
- 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.
- Graduation Semester
- 2022-05
- Type of Resource
- Thesis
- Copyright and License Information
- Copyright 2022 Lindsay Chatkewitz
Owning Collections
Graduate Dissertations and Theses at Illinois PRIMARY
Graduate Theses and Dissertations at IllinoisManage Files
Loading…
Edit Collection Membership
Loading…
Edit Metadata
Loading…
Edit Properties
Loading…
Embargoes
Loading…