Open Collections

Hoang, Christopher

University of British Columbia

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine involved in the TSLP signaling pathway which is important in the activation of the type 2 immune response. TSLP has been implicated in diseases with an underlying dysregulation of the type 2 immune response, including atopic dermatitis (AD). Currently, approved therapeutics for AD focus on targeting downstream effectors of the TSLP pathway, with no effective therapy targeting TSLP or the TSLP receptor (TSLPR) directly. This thesis aims to develop small molecule inhibitors against TSLP signaling by targeting the TSLPR, with the overall goal of creating a topical therapy for AD. To build on previous work completed on this project, Chapter 2 continued the hit expansion process by incorporating different chemical features into the hit scaffold. Compounds were screened in HuT78 T-cells to investigate their impact on TSLP-induced cytokine production using enzyme-linked immunosorbent assays. While some compounds exhibited cytokine inhibition compared to the vehicle control, none outperformed a previously identified top compound BP79. In Chapter 3, optimization of the top compound BP79 was explored by functionalizing the terminal amide of the scaffold. Characterization of a crucial intermediate allowed for a synthetic route to be devised to generate BP79 analogs. Screening of the analogs in HuT78 T-cells revealed that many analogs exhibited equivalent levels of inhibition to BP79 at concentrations as low as 1µM. Differential inhibitor potencies were only observed when screened in primary CD4+ T-cells at nanomolar concentrations. At best, some of the modifications on BP79 explored were tolerated with cytokine inhibition at comparable levels to BP79 in the nanomolar concentrations, with many of the modifications consisting of non-polar aromatic and aliphatic rings. While some modifications were tolerated, no major improvements to the potency of BP79 were achieved. Overall, the best-performing analogs synthesized may serve as other potential drug candidates should BP79 encounter translational challenges in future experiments. The novelty of these compounds also allows for intellectual property claims down the line if they proceed into further clinical development and commercialization as a drug.

Text

2025-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86943

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/