Synthesis and evaluation of CYP27A1 inhibitors and NR0B2 agonists as anticancer immunomodulators

Immune checkpoint inhibition has revolutionized the landscape of cancer treatment, affording durable, long term tumor regression by harnessing the innate power of the immune system. Despite the success of immune checkpoint inhibitors, the majority of patients receiving this type of treatment do not glean clinical benefit; thus, there exists a strong impetus to find strategies to improve immune checkpoint inhibition. To address this clinical gap, the development of two separate classes of small molecule immunomodulators was pursued. CYP27A1 has emerged as a potential target for cancer therapy due to its impact on breast and ovarian tumor progression and metastasis via synthesis of the immunosuppressive metabolite 27-hydroxycholesterol. Though inhibition of CYP27A1 displays synergy with immune checkpoint inhibition in vivo there is a dearth of known CYP27A1 inhibitors. To address this deficiency, a suite of compounds was synthesized to assess the structure activity relationship of literature reported CYP27A1 inhibitors. Efforts to develop a whole cell metabolite reduction assay are also described herein. Nuclear receptor NR0B2 has been identified as a key mediator of immune response in myeloid cells by biasing T cells towards an immunostimulatory rather than an immunosuppressive phenotype. Discovery of the small molecule NR0B2 agonist DSHN revealed that this tuning of T cell response can result in powerful antitumor effects in murine breast cancer models. DSHN, despite its activity, has properties that limit its translational potential, so a library of DSHN analogs was synthesized and evaluated to address this limitation. These efforts resulted in discovery of DSHN-OMe, a compound that displays potent antitumor activity in several murine breast cancer models.

Name thesis:degree_name

M.S.

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2024

Author dc:creator

• Albright, Samuel Townsend

Contributors dc:contributor

• Hergenrother, Paul J.

• Oncology
• Immunomodulators

Statement dc:rights

• Copyright 2024 Samuel Albright

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/125744

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F125744