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Structural and biochemical insights into the mechanism of action of the clinical USP1 inhibitor, KSQ-4279
DOI:
10.1021/acs.jmedchem.4c01184
Authors:
Martin L.
Rennie
(University of Glasgow)
,
Mehmet
Gundogdu
(Ubiquigent Ltd)
,
Connor
Arkinson
(University of Glasgow)
,
Steven
Liness
(Ubiquigent Ltd)
,
Sheelagh
Frame
(Ubiquigent Ltd)
,
Helen
Walden
(University of Glasgow)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Journal Of Medicinal Chemistry
State:
Published (Approved)
Published:
August 2024
Diamond Proposal Number(s):
34071
Open Access
Abstract: DNA damage triggers cell signaling cascades that mediate repair. This signaling is frequently dysregulated in cancers. The proteins that mediate this signaling 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-like pocket in USP1. Our results contribute to the understanding of the mechanism of action of USP1 inhibitors at the molecular level.
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Diamond Offline Facilities:
Electron Bio-Imaging Centre (eBIC)
Instruments:
Krios IV-Titan Krios IV at Diamond
Added On:
28/08/2024 14:32
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Chemistry
Structural biology
Life Sciences & Biotech
Technical Tags:
Microscopy
Electron Microscopy (EM)
Cryo Electron Microscopy (Cryo EM)