Investigating the Anti-Cancer Effects of Small Molecule MEI-1 as a Potential MDM2 Inhibitor

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dc.contributor.advisorSheng, Yi
dc.contributor.authorIlic, Viktoria Katarina
dc.date.accessioned2021-11-15T15:15:42Z
dc.date.available2021-11-15T15:15:42Z
dc.date.copyright2020-09
dc.date.issued2021-11-15
dc.date.updated2021-11-15T15:15:41Z
dc.degree.disciplineBiology
dc.degree.levelMaster's
dc.degree.nameMSc - Master of Science
dc.description.abstractMDM2 is an oncogenic E3 ligase found to be overexpressed in a number of human cancers, leading to poor prognosis. MDM2 overexpression inhibits the function of the tumour suppressor p53, which ubiquitinates p53 and tags it for proteasomal degradation. MDM2 also exhibits p53-independent oncogenic activities through targeting other tumour suppressor proteins, such as Foxo3a and Rb. Thus, a preferred strategy in anti-cancer therapeutic development is to inhibit MDM2 in cancer cells. A small molecule MEI-1 was identified through in silico screening targeting the MDM2 catalytic RING domain. The purpose of this project was to explore the anti-cancer effects of MEI-1 in a number of tested cancer lines including leukemia, breast carcinoma, osteosarcoma, and colorectal cancers. Using biochemical and cellular assays, MEI-1 was found to induce apoptosis and inhibit MDM2 E3 ligase activity in leukemia and colorectal cancer cell lines. MEI-1 was shown to block MDM2-mediated ubiquitination and de-stabilize MDM2/MDMX, causing p53 stabilization and activation. Additionally, MEI-1 was shown to affect the stability of Foxo3a and Rb as both were reported to be MDM2 E3 ligase substrates. Lastly, MEI-1 was shown to physically bind with the recombinant MDM2: MDMX RING domain heterodimer using Biolayer Interferometry technology. These results provide biochemical and cellular evidence suggesting MEI-1 is a promising small molecule with anti-cancer effects through targeting MDM2. This study also reveals that inhibition of MDM2 through disrupting the MDM2:MDMX heterodimer could be a plausible approach for the development of MDM2 inhibitors as potential anti-cancer therapeutic agents.
dc.identifier.urihttp://hdl.handle.net/10315/38638
dc.languageen
dc.rightsAuthor owns copyright, except where explicitly noted. Please contact the author directly with licensing requests.
dc.subjectOncology
dc.subject.keywordsE3 ligase
dc.subject.keywordsAML-2
dc.subject.keywordsHL-60
dc.subject.keywordsHCT-116
dc.subject.keywordsLeukaemia
dc.subject.keywordsColorectal cancer
dc.subject.keywordsCancer
dc.subject.keywordsMDM2
dc.subject.keywordsp53
dc.subject.keywordsp53-independent activity
dc.subject.keywordsMDM2 overexpression
dc.subject.keywordsTumour suppressor
dc.subject.keywordsUbiquitin
dc.subject.keywordsUbiquitination
dc.subject.keywordsFoxo3a
dc.subject.keywordsRb
dc.subject.keywordsAnti-cancer therapeutic
dc.subject.keywordsMDM2 inhibitor
dc.subject.keywordsBreast cancer
dc.subject.keywordsOsteosarcoma
dc.subject.keywordsApoptosis
dc.subject.keywordsAnti-cancer effects
dc.subject.keywordsSmall molecule
dc.titleInvestigating the Anti-Cancer Effects of Small Molecule MEI-1 as a Potential MDM2 Inhibitor
dc.typeElectronic Thesis or Dissertation

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