DOI
https://doi.org/10.25772/6T49-HZ94
Defense Date
2021
Document Type
Thesis
Degree Name
Master of Science
Department
Biochemistry
First Advisor
Swati Palit Deb
Abstract
TP53 is the most commonly mutated tumor suppressor gene and is mutated in 50% of all cancers and up to 70% of lung cancers. When p53 is mutated, it loses its tumor suppressor function and can also gain new oncogenic functions, such as increased cell proliferation, tumorigenicity and chemoresistance. Previous studies have shown that cancer cells containing gain-of-function (GOF) p53 mutations depend on its transactivation function for cell proliferation and tumor formation. We hypothesized that small molecule inhibitors impeding GOF p53-mediated transactivation should selectively inhibit GOF p53-induced oncogenesis. In this study, we employed a novel detection system to screen chemical libraries for compounds that inhibit GOF p53-mediated transactivation. We identified four compounds that selectively inhibited GOF p53-mediated transcription. These compounds are GF 109203X, 2-Amino-N-[[4-(5-bromopyrimidin-2-yl)oxy-3-chlorophenyl]carbomoyl] benzamide, UNC 2881 and SC 144 hydrochloride. Through growth assays, we also found that GF 109203X and SC 144 hydrochloride selectively inhibited the growth of lung cancer cells containing GOF p53. This suggests a potential mechanistic link between GOF p53-mediated transactivation and GOF p53-induced oncogenesis. Inhibition of the transactivation function of GOF p53 using these compounds may be useful in the development of lung cancer treatments.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-12-2021