Inhibition of Retinoblastoma Protein Inactivation
Technical Report,01 Sep 2014,31 Aug 2017
University of California, Santa Cruz Santa Cruz United States
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The objective of this project is to discover and characterize molecules that inhibit breast cancer cell proliferation by maintaining activity of the retinoblastoma protein Rb. Rb is inactivated to drive proliferation in normal and cancer cells by phosphorylation, which dissociates the E2F transcription factor from Rb to activate S phase genes. Our goal is to find and characterize molecules that stabilize the complex between phosphorylated Rb and E2F. During the project period, we tested our proposed mechanism for how molecules may enhance the affinity of phosphorylated Rb phosRb for E2F by disrupting the compact phosRb conformation. We identified a proof-of-concept peptide that increases phosRb-affinity, we developed a fluorescence-based assay to identify small molecule enhancers of phos-Rb affinity, we performed a high throughput screen and further tested hits in the primary screen, and we began pursuing additional fragment-based approaches to identifying lead compounds.
- Medicine and Medical Research
- Genetic Engineering and Molecular Biology