Biophysical and structural characterization ofBTB domain proteins Kaiso and Mizl
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The central role deregulated protein-protein interactions (PPIs) play in human disease make PPIs important targets for drug discovery efforts. PPI interfaces have historically been difficult to disrupt using drug-mediated therapy, but Fragment-Based Drug Discovery (FBDD) has proven to be a useful approach for identifying tractable PPIs that are amenable to drug discovery efforts, and, subsequently, optimizing fragment-like, small molecules that block PPIs of interest. Many PPIs are implicated in oncogenesis, so targeting these PPIs may hold promise in the development of anti-cancer therapeutics. Proteins of the Bric-a-brac Tramtrack Broad complex (BTB) domain family, specifically, are strongly implicated in a variety of cancers, making them attractive targets. In this study, we biophysically and structurally characterized two proteins of the BTB domain family: Mizl and Kaiso. We used a FBDD approach, beginning with a Fragment-Based Screening (FBS) campaign to assess the possibility oftargeting Mizl and Kaiso with small molecule inhibitors. We identified a broad range of chemically distinct fragment like, small-molecule ligands for the BTB domain of Mizl (MizlBTB). This contrasts with KaisoBTB, for which no ligands were identified. We then quantified binding of four fragment "hits" from the MizlBTB screen with the highest affinities. Finally, we solved the crystal structure of MizlBTB, and observed a large, solvent-exposed, hydrophobic pocket, which may explain the relatively high number ofFBS "hits". This work provides a foundation for further optimization of small molecule inhibitors for MizlBTB, and reports variability in structures that may contribute to pronounced differences in the ability to target two highly-conserved proteins of the same domain family with small molecule inhibitors.