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Buhrlage Lab - Cancer Chemical Biology

Sara Buhrlage, PhD
CANCER CHEMICAL BIOLOGY

Our Research

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DUB inhibitor development
Deubiquitinating enzymes (DUBs) are peptidases that cleave the isopeptide bond between the C-terminus of ubiquitin and their substrate, removing ubiquitin from target proteins. Since the ubiquitin post-translational modification is essential for regulating protein degradation, activity, localization, and more, the ability to modulate DUB activity with small molecules has broad clinical and research applications. Therapeutically, DUBs have been implicated in diverse indications encompassing oncology, neurodegeneration, and infectious diseases. Excitingly, inhibiting DUBs offer the potential to degrade pathogenic proteins in a targeted manner.
 
Our lab takes a target class approach to develop potent and selective DUB inhibitors. 
We harness the power of diverse and complementary techniques for inhibitor discovery: high throughput screening, chemoproteomics, medicinal chemistry, biochemistry, computational chemistry, bioinformatics, and structural analysis. This orthogonal approach has a well-proven track record in the inhibitor development against well-studied enzyme classes, such as serine hydrolases and kinases. As an example, we developed a subnanomolar covalent USP7 inhibitor, which elicits cell death in Ewing sarcoma and malignant rhabdoid tumor models through a p53-dependent mechanism. (Schauer et al. 2020 Sci. Rpts.)



Uncovering function and clinical relevance of DUBs
While there are 100 DUBs identified in the human proteome, the substrate scope, biological function, and clinical relevance of most DUB family members are still poorly characterized. To facilitate the characterization of these features, our lab employs the use of reported inhibitors, curated libraries, and compounds developed in house. We use these small molecule probes to carry out phenotypic screens to identify DUB inhibitors with therapeutically relevant activity. This is followed by validation and mechanistic work to identify DUBs of interest and characterize compound mechanism of action. We also undertake large-scale bioinformatic studies to generate and mine datasets to elucidate DUB function. 
 
A significant value in targeting DUBs is the ability to reach "undruggable" targets, and preferentially targeting oncogenic mutants of proteins over their wildtype counterparts. By screening for inhibitors targeting specific proteins in model cell lines, our lab has identified DUB inhibitors which induce degradation of oncogenic mutant tyrosine kinase FLT3 in acute myeloid leukemia. Target deconvolution studies revealed USP10 is the DUB target relevant for the phenotype. (Weisberg et al. 2017 Nat. Chem. Biol.)

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