Author ORCID Identifier
Date Available
5-13-2024
Year of Publication
2023
Degree Name
Master of Science (MS)
Document Type
Master's Thesis
College
Pharmacy
Department/School/Program
Pharmaceutical Sciences
First Advisor
Dr. R. Kip Guy
Second Advisor
Dr. Jared Hammill
Abstract
Ubiquitin (UB) and ubiquitin-like protein (UBL) pathways have emerged as important targets for oncology drug discovery based on the success of proteasome inhibitors (bortezomib or carfilzomib), E3 inhibitors, and the NEDD8 E1 inhibitor pevonedistat (MLN42924). Chemical inhibitors have also proven to be useful probes for identifying and dissecting multifactor UB and UBL regulatory networks. Toward this end, we have pursued approaches to target NEDD8 ligation to Cullins, through developing small molecule inhibitors of DCN1 (defective in Cullin Neddylation 1). DCN1 was discovered as a potentiating RBX1-dependent NEDD8-ligation, through recognizing the acetylated N-terminal methionine of the NEDD8 E2s UBE2M and UBE2F. The DCN1 gene was also discovered to undergo frequent chromosomal amplifications and associated with poor prognosis in squamous cell carcinomas and other cancers. To date, we have conducted a high-throughput screening campaign of ~500,000 compounds and have identified three unique chemical series for optimization.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2023.223
Funding Information
National Institute of Health CA247365
Recommended Citation
Kovalic, Leah, "Optimization of Orally Bioavailable Inhibitors of Defective in Cullin Neddylation 1 (DCN-1)" (2023). Theses and Dissertations--Pharmacy. 148.
https://uknowledge.uky.edu/pharmacy_etds/148
Included in
Medicinal and Pharmaceutical Chemistry Commons, Oncology Commons, Pharmaceutics and Drug Design Commons
