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bioRxiv · 10.1101/2024.05.16.594330

Structural and biochemical insights on the mechanism of action of the clinical USP1 inhibitor, KSQ-4279

Rennie, M. L.·Gundogdu, M.·Arkinson, C.·Liness, S.·Frame, S.·Walden, H.
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Abstract

DNA damage triggers cell signalling cascades that mediate repair. This signalling is frequently dysregulated in cancers. The proteins that mediate this signalling are potential targets for therapeutic intervention. Ubiquitin-specific protease 1 (USP1) is one such target, with small molecule inhibitors already in clinical trials. Here we use biochemical assays and cryo-electron microscopy (cryo-EM) to study the clinical USP1 inhibitor, KSQ-4279 (RO7623066), and compare this to the well-established, tool compound, ML323. We find that KSQ-4279 binds to the same cryptic site of USP1 as ML323 but disrupts the protein structure in subtly different ways. Inhibitor binding drives a substantial increase in thermal stability of USP1, which may be mediated through the inhibitors filling a hydrophobic tunnel in USP1. Our results contribute to the understanding of the mechanism of action of USP1 inhibitors at the molecular level.

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Rennie, M. L., Gundogdu, M., Arkinson, C., Liness, S., Frame, S., Walden, H.. 2024-05-16. Structural and biochemical insights on the mechanism of action of the clinical USP1 inhibitor, KSQ-4279. https://doi.org/10.1101/2024.05.16.594330

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