The public defence will be held as a video conference over Zoom.
The defence will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.
Click here to participate in the public defence
Due to copyright reasons, an electronic copy of the thesis must be ordered from the faculty. In order for the faculty to have time to process the order, it must be received by the faculty no later than 2 days prior to the public defence. Orders received later than 2 days before the defence will not be processed. Inquiries regarding the thesis after the public defence must be addressed to the candidate.
Digital Trial Lecture – time and place
Adjudication committee
- First opponent: Assistant Professor Dong-Hua Yang, St. John's University, USA
- Second opponent: Professor Guanglin Cui, Nord University
- Third member and chair of the evaluation committee: Head of Group Judith Staerk, University of Oslo
Chair of the Defence
Professor Lars Nilsson, University of Oslo
Principal Supervisor
Professor Ole Andreassen, University of Oslo
Summary
Ubiquitin-proteasome system is essential in maintaining cellular protein homeostasis by regulating the degradation of intracellular proteins. Like ubiquitination, neddylation transfers the ubiquitin-like protein NEDD8 to its target proteins and thus regulates their functions.
Hyperactivation of Neddylation has been recognized in various cancer types, which draws much attraction for oncologic drug discovery.
DCN1, as a co-E3 ligase, interacts with UBC12 to enhance neddylation efficiency and this interaction has emerged as a therapeutic target for cancer treatment. Therefore, in this project, we aimed to discover novel DCN1 inhibitors, and evaluate their potential anti-cancer effects.
Two in vitro DCN1-UBC12 interaction small molecular screening systems were established before they were used to screen the compounds library. After screening, two novel hit compounds with two new scaffolds in their structures were identified: DC-1 with a 5-cyano-6-phenylpyrimidin core, and 5a with a phenyltriazole thiol core.
Further optimization which based on the structures of the hit compounds uncovered three more potent inhibitors: DC-2, SK-464 and HZX-960. Using protein and cellular thermal shift assays, bioLayer interferometry, etc, inhibitors were identified to bind to DCN1 at both protein and cellular levels, resulting in the decrease of cullin3 neddylation and the accumulation of Nrf2.
Biologically, DC-2 inhibited the proliferation of three lung cancer cell lines with DCN1 over-expression. SK-464 hindered the migration and invasion of two squamous carcinoma cell lines which DCN1 were highly expressed. Furthermore, HZX-960 attenuated liver fibrotic signaling in liver fibrosis, where DCN1 was found to be elevated in liver fibrotic cells and tissues.
In summary, three novel inhibitors targeting DCN1-UBC12 interaction were discovered and assessed. These results may shed a light on the new strategies for cancer therapy and liver fibrosis treatment.
Additional information
Contact the research support staff.