Structural and Biochemical Insights into the Mechanism of Action of the Clinical USP1 Inhibitor, KSQ-4279.

J Med Chem

School of Molecular Biosciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.

Published: September 2024

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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11403619PMC
http://dx.doi.org/10.1021/acs.jmedchem.4c01184DOI Listing

Publication Analysis

Top Keywords

mechanism action
8
clinical usp1
8
usp1 inhibitor
8
inhibitor ksq-4279
8
usp1
7
structural biochemical
4
biochemical insights
4
insights mechanism
4
action clinical
4
ksq-4279 dna
4

Similar Publications

Introduction: The risk of HCC is twice as high in diabetic patients compared to non-diabetic ones, suggesting that diabetes advances carcinogenesis in the liver through a variety of mechanisms. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to improve liver outcomes, emerging as promising agents to treat hepatocellular carcinoma (HCC) in patients with type 2 diabetes mellitus (T2DM).

Methods: We searched PubMed and Scopus databases for articles presenting an association between SGLT2is and HCC to explore the putative mechanisms of action underlying the anti-proliferative activity of SGLT2is.

View Article and Find Full Text PDF

Herein, we present a distorted square pyramidal mercury complex, [HgII(L)Cl] (1), based on a quinoline-substituted formazan ligand LH[3-Cyano-1,5-(quinolin-8-yl)formazan], which was evaluated for its anti-bacterial activity in vitro. Complex 1 was prepared by refluxing 3-Cyano-1,5-(quinolin-8-yl)formazan ligand and mercury chloride(II) in equimolar quantity and was characterized utilizing a range of analytical methods, including single crystal X-ray diffraction (SCXRD) technique. The crystal packing in complex 1 has been elucidated using supramolecular investigations, which have shown the presence of fascinating Hg-Cl···Hg intermolecular spodium bonds of the order 3.

View Article and Find Full Text PDF

Role of arbutin in the inhibition of FBXO5 in hepatocellular carcinoma.

Discov Oncol

December 2024

Department of Hygiene, School of Public Health, Bengbu Medical University, Bengbu, 233030, Anhui, People's Republic of China.

Purpose: This work investigated the effect of FBXO5 in hepatocellular carcinoma (HCC) and the mechanism of action of arbutin in its inhibition.

Methods: FBXO5 mRNA and protein expressions in the tumor were assessed using TCGA, ICGC and HPA databases. Cox regression analysis and Kaplan-Meier survival curves were employed to assess the impact of FBXO5 on the survival outcomes of patients with HCC.

View Article and Find Full Text PDF

Single-Atom based Metal-Organic Frameworks for Efficient C-S Cross-Coupling.

Chem Asian J

December 2024

IOCB CAS: Ustav organicke chemie a biochemie Akademie ved Ceske republiky, Chemistry, 16000, CZECHIA.

Single-atom-based Metal-Organic Frameworks (MOFs) hold great promising candidates for heterogeneous catalysis, demonstrating outstanding catalytic activity and exceptional product selectivity. This is attributed to their optimal atom utilization, high surface energy, and the presence of unsaturated coordination environments. Here in, we have developed a nickel single-atom catalyst (UiO-66/Ni) featuring Ni single atoms covalently attached to defect-engineered Zr-oxide clusters within the stable UiO-66 framework, synthesized via a straightforward solution impregnation method.

View Article and Find Full Text PDF

In a warming world, it is crucial to understand how rising temperature affects the physiology of organisms. To investigate the effect of a warming environment on the metabolism of heterothermic bats during the costly lactation period, we characterised metabolic rates in relation to roost temperature, the bats' thermoregulatory state (normothermia or torpor), time of day and age of juveniles. In a field experiment, we heated the communal roosts of a wild colony of Bechstein's bats (Myotis bechsteinii) every other day while measuring metabolic rates using flow-through respirometry.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!