Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors

O'Dowd, Colin; Helm, Matthew; Rountree, J. S. Shane; Flasz, Jakub; Arkoudis, Elias; Miel, Hugues; Hewitt, Peter R.; Jordan, Linda; Barker, Oliver; Hughes, Caroline; Rozycka, Ewelina; Cassidy, Eamon; McClelland, Keeva; Odrzywol, Ewa; Page, Norbert P.; Feutren-Burton, Stephanie; Dvorkin, Scarlett; Gavory, Gerald; Harrison, Timothy

doi:10.1021/acsmedchemlett.7b00512

Cited by 52 publications

(41 citation statements)

References 22 publications

(49 reference statements)

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“…2g). All new generation USP7 inhibitors, including Almac4 30 , Almac47 32 , P50429 31 , FT671 29 , and GNE-6776 33 , increased STF reporter. Early generation of USP7 inhibitors P5091 34 , P22077 35 , and HBX41108 36 decreased STF reporter, as reported earlier 23,24 .…”

Section: Resultsmentioning

confidence: 96%

USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin

Lü

Zamponi

et al. 2019

Nat Commun

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Axin is a key scaffolding protein responsible for the formation of the β-catenin destruction complex. Stability of Axin protein is regulated by the ubiquitin-proteasome system, and modulation of cellular concentration of Axin protein has a profound effect on Wnt/β-catenin signaling. Although E3s promoting Axin ubiquitination have been identified, the deubiquitinase responsible for Axin deubiquitination and stabilization remains unknown. Here, we identify USP7 as a potent negative regulator of Wnt/β-catenin signaling through CRISPR screens. Genetic ablation or pharmacological inhibition of USP7 robustly increases Wnt/β-catenin signaling in multiple cellular systems. USP7 directly interacts with Axin through its TRAF domain, and promotes deubiquitination and stabilization of Axin. Inhibition of USP7 regulates osteoblast differentiation and adipocyte differentiation through increasing Wnt/β-catenin signaling. Our study reveals a critical mechanism that prevents excessive degradation of Axin and identifies USP7 as a target for sensitizing cells to Wnt/β-catenin signaling.

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Section: Resultsmentioning

confidence: 96%

USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin

Lü

Zamponi

et al. 2019

Nat Commun

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“…The inhibitor in complex with the USP7 catalytic domain reveals that binding occurs about 5 Å from the catalytic triad ( Lamberto et al, 2017 ). Similarly, the non-covalent pyrimidine-based USP7 inhibitor Compound 46 binds a few angstroms from the active site residues ( O’Dowd et al, 2018 ).…”

Section: Usp7: Links With Cancermentioning

confidence: 99%

USP7 Is a Master Regulator of Genome Stability

Valles

Bezsonova

Woodgate

et al. 2020

Front. Cell Dev. Biol.

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Genetic alterations, including DNA mutations and chromosomal abnormalities, are primary drivers of tumor formation and cancer progression. These alterations can endow cells with a selective growth advantage, enabling cancers to evade cell death, proliferation limits, and immune checkpoints, to metastasize throughout the body. Genetic alterations occur due to failures of the genome stability pathways. In many cancers, the rate of alteration is further accelerated by the deregulation of these processes. The deubiquitinating enzyme ubiquitin specific protease 7 (USP7) has recently emerged as a key regulator of ubiquitination in the genome stability pathways. USP7 is also deregulated in many cancer types, where deviances in USP7 protein levels are correlated with cancer progression. In this work, we review the increasingly evident role of USP7 in maintaining genome stability, the links between USP7 deregulation and cancer progression, as well as the rationale of targeting USP7 in cancer therapy.

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“…Enantiomers were retained for enhanced sampling. The activity of the 46 USP7 inhibitors [12a] were divided based on active and inactive molecules with pIC 50 values cutoffs of 6.1 and 3.4 accordingly. The pharmacophore sites, for each conformer generated from every ligand, were created and these sites were used to generate common pharmacophores using the 9 active ligands with pIC 50 above 6.1.…”

Section: Methodsmentioning

confidence: 99%

An Integrated in silico Approach and in vitro Study for the Discovery of Small‐Molecule USP7 Inhibitors as Potential Cancer Therapies

Kanan

Doğan

et al. 2020

ChemMedChem

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The ubiquitin‐specific protease 7 (USP7) is a highly promising well‐validated target for a variety of malignancies. USP7 is critical in regulating the tumor suppressor p53 along with numerous epigenetic modifiers and transcription factors. Previous studies showed that USP7 inhibitors led to increased levels of p53 and anti‐proliferative effects in hematological and solid tumor cell lines. Thus, this study aimed to identify potent and safe USP7 hit inhibitors as potential anti‐cancer therapeutics via an integrated computational approach that combines pharmacophore modeling, molecular docking, molecular dynamics (MD) simulations and post‐MD free energy calculations. In this study, the crystal structure of USP7 has been extensively investigated using a combination of three different chemical pharmacophore modeling approaches. We then screened ∼220.000 drug‐like small molecule library and the hit ligands predicted to be nontoxic were evaluated further. The identified hits from each pharmacophore modeling study were further examined by 1‐ns short MD simulations and MM/GBSA free energy analysis. In total, we ran 1 ns MD simulations for 1137 selected on small compounds. Based on their average MM/GBSA scores, 18 ligands were selected for 50 ns MD simulations along with one highly potent USP7 inhibitor used as a positive control. The in vitro enzymatic inhibition assay testing of our lead 18 molecules confirmed that 7 of these molecules were successful in USP7 inhibition. Screening results showed that within the used screening approaches, the most successful one was structure‐based pharmacophore modeling with the success rate of 75 %. The identification of potent and safe USP7 small molecules as potential inhibitors is a step closer to finding appropriate effective therapies for cancer. Our lead ligands can be used as a scaffold for further structural optimization and development, enabling further research in this promising field.

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Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors

Cited by 52 publications

References 22 publications

USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin

USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin

USP7 Is a Master Regulator of Genome Stability

An Integrated in silico Approach and in vitro Study for the Discovery of Small‐Molecule USP7 Inhibitors as Potential Cancer Therapies

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