Out now! The latest paper from the lab, spearheaded by Philipp Schenk, describing a new USP9X inhibitor with a unique DUB binding site.
Komander Lab
USP9X: understanding its cell-type-specific deubiquitination targets & mitotic arrest phenotypes in cancer cells
Broad cancer cell-line screen by Philipp Schenk et al @komanderlab.bsky.social @wehi-research.bsky.social upon treatment with next-gen inhibitor WEHI-092
link.springer.com/article/10.1...
The ubiquitin-specific protease (USP) USP9X is a human deubiquitinase (DUB) with a large number of described targets and cellular roles. In cancer, USP9X is found as an oncogene or as a tumour suppressor depending on context, and its utility as a target for cancer therapy remains unclear. We here describe WEHI-092, a piperazine-based USP9X-specific small-molecule inhibitor, which binds to a unique region in the USP9X Fingers-subdomain, distinct from known DUB-inhibitor binding sites. Using proteomics and ubiquitinomics, we show that USP9X targets distinct substrates compared to USP7, yet the substrate profile of USP9X varies significantly across cancer cell lines. We reveal a core set of 17 proteins commonly regulated by USP9X in most cell lines, which we consider as proximal biomarkers for USP9X inhibition. Consistent with proteomics, we show in unrelated cell lines that WEHI-092 treatment arrests the cell cycle in metaphase without inducing cell death. This explains growth suppression in long-term clonogenic assays in most cancer cell lines, and positions USP9X inhibitors as a new class of selective mitotic poisons.
