Open Collections

Foo, Jane Wei Ling

University of British Columbia

The development of diverse cancers is often driven by the dysregulated activity of transcription factors (TFs) that control the expression of genes associated with proliferation, differentiation, and invasion. Prostate cancer (PCa) and breast cancer (BCa) are usually dependent on steroid hormone nuclear receptors signaling, specifically the androgen receptor (AR) in PCa and the estrogen receptor (ER) in BCa. This dependence has prompted the development of various hormonal therapies targeting the AR and the ER in PCa and BCa, respectively. While these treatments are initially effective, the cancer eventually recurs, with the dysregulation of additional TFs, such as Gli and N-Myc, implicated in therapeutic resistance and disease progression. This thesis aims to develop small-molecule inhibitors that interfere with crucial TF protein-protein and protein-DNA interactions, by using a combination of computer-aided drug design (CADD), cell-based characterization, and biophysical assays. We characterized a non-canonical function of the AR, where its binding to Gli facilitates the activation of Gli transcription and the progression of PCa to castration-resistant disease. Considering Gli’s role in driving cancer cell growth and the significance of AR activation in this pathway, targeting their interaction would provide a new strategy to inhibit PCa progression. Our work on N-Myc, a TF long deemed “undruggable,” led to the development of a first-in-class inhibitor (VPC-70619) that prevents its binding to DNA E-boxes, leading to decreased proliferation of N-Myc driven cancer models. Finally, advanced BCa therapies like antiestrogens, target the estrogen binding site in ER, but commonly fail due to resistance. By targeting the interaction between ER and its coactivators at an allosteric site, we identified a compound (VPC-260724) that overcomes therapeutic resistance and inhibit the growth of tamoxifen resistant BCa models. Our exploration of TF interactions, namely those involving ER, AR, Gli, and N-Myc, not only sheds light on the molecular mechanisms driving PCa and BCa, but also lays the foundation for the development of innovative therapeutic strategies. The design of small molecules through CADD and robust experimental validation offers a promising approach to revolutionizing the landscape of cancer therapeutics and to develop more effective targeted treatments against advanced stages of these diseases.

Text

2024-04-18

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/87878

Interdisciplinary Oncology

University of British Columbia

UBCV

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