Identification of Small Non-Peptidic Ligands that Bind the Scf-beta- TRCP Ubiquitin Ligase to Target to ER for Ubiquitination and Degradation

摘要

Breast cancer is the most common cancer diagnosed among women. Breast cancer cells often require activation of the estrogen-specific steroid hormone receptor by estrogen to proliferate, and it is well known that steroid hormone receptor signaling plays a pivotal role in progression of breast cancer disease. We hypothesize that a completely novel conceptual approach known as Protac (Proteolysis Targeting Chimeric Molecule) will lead to the ubiquitination and degradation of targeted proteins. Protacs contain at one end, the I kappa B alpha phosphopeptide that binds to a ubiquitin ligase SCF beta (TRCP) and at the other end, the ligand estradiol. We previously demonstrated that Protacs promote the ubiquitination and degradation of ER and AR in vitro and in vivo, respectively. While we have demonstrated that a phosphopeptide containing Protac is effective, this compound is not likely to be cell membrane- permeable. The overall goal is to test the hypothesis that small non-peptidic ligands that bind SCF beta (TRCP) can be used to generate estrogen-based Protacs that mediate ER ubiquitination and degradation. In Aim 1, we will express recombinant Beta-TRCP. In Aim 2, we will screen a chemical library for molecules that bind Beta-TRCP. Potential "hits" we will used to develop new Protacs that will be tested for effects on ER ubiquitination and degradation in breast cancer cells. Protacs provide a novel approach to the treatment of breast cancer.