Expand the drug discovery toolbox to target Macrophage migration inhibitory factor in cancer

Zhangping Xiao

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Samenvatting

Lung cancer is the leading cause of cancer-related death worldwide, claiming 1.8 million victims (257, 000 in EU) in 2020. To unleash the capability of targeted therapy for lung cancer, which is limited by the heterogeneity and acquired drug resistance, it is imperative to discover and exploit previously unrecognized molecular mechanisms involved in cancer cell proliferation. A protein with a putatively central role in such mechanisms is macrophage migration inhibitory factor (MIF). To advance MIF-directed research, we leveraged medicinal chemistry and chemical biology approaches to develop small-molecule tools to explore its potential as drug target. MIF possesses various enzyme active sites and protein-protein interaction sites. We addressed the tautomerase active site, which overlaps with the CD74 receptor-binding site, by a novel fluorophore, which is capable to interfere with the MIF-CD74 interaction, and its fluorescent properties were utilized for development of a competition-based assay format to quantify binding to the MIF. Also for the MIF analogue, MIF2 small molecule modulators were developed. We developed the first potent MIF2 tautomerase inhibitor that exhibits robust inhibition on growth of lung cancer cells. Furthermore, a high affinity binder for the MIF tautomerase active site was employed to develop a novel potent MIF-targeted proteolysis targeting chimera (PROTAC), which enables elimination of MIF and inhibition of the proliferation of cancer cells. In addition, we developed fluorescent probes to facilitate cellular translocation studies on MIF and MIF2. Taken together, we provided a novel set of MIF-directed probes including several potential lung cancer therapeutics.
Originele taal-2English
KwalificatieDoctor of Philosophy
Toekennende instantie
  • Rijksuniversiteit Groningen
Begeleider(s)/adviseur
  • Dekker, Frank, Supervisor
  • Quax, W. J., Supervisor
Datum van toekenning12-okt.-2021
Plaats van publicatie[Groningen]
Uitgever
DOI's
StatusPublished - 2021

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