Mar 27, 2020

Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism

Scientific Reports
Nathan J SchauerSara J Buhrlage


Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from specific protein substrates in order to alter their degradation rate and sub-cellular localization. USP7 has been proposed as a therapeutic target in several cancers because it has many reported substrates with a role in cancer progression, including FOXO4, MDM2, N-Myc, and PTEN. The multi-substrate nature of USP7, combined with the modest potency and selectivity of early generation USP7 inhibitors, has presented a challenge in defining predictors of response to USP7 and potential patient populations that would benefit most from USP7-targeted drugs. Here, we describe the structure-guided development of XL177A, which irreversibly inhibits USP7 with sub-nM potency and selectivity across the human proteome. Evaluation of the cellular effects of XL177A reveals that selective USP7 inhibition suppresses cancer cell growth predominantly through a p53-dependent mechanism: XL177A specifically upregulates p53 transcriptional targets transcriptome-wide, hotspot mutations in TP53 but not any other genes predict response to XL177A across a panel of ~500 cancer cell lines, and TP53 knockout rescues XL177A-mediated growth suppression of T...Continue Reading

  • References
  • Citations


  • We're still populating references for this paper, please check back later.
  • References
  • Citations


  • This paper may not have been cited yet.

Mentioned in this Paper

Genetic Hotspot
Suppression, Genetic
Protein p53
Cell Growth
Cellular Localization
PTEN protein, human
MYCN protein, human
FOXO4 wt Allele
Transcription, Genetic

Trending Feeds


Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Synthetic Genetic Array Analysis

Synthetic genetic arrays allow the systematic examination of genetic interactions. Here is the latest research focusing on synthetic genetic arrays and their analyses.

Autism: Motor Learning

A common feature of autism spectrum disorder (ASD) is the impairment of motor control and learning, consistent with perturbation in cerebellar function. Find the latest research on ASD and motor learning here.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

Sexual Dimorphism in Neurodegeneration

There exist sex differences in neurodevelopmental and neurodegenerative disorders. For instance, multiple sclerosis is more common in women, whereas Parkinson’s disease is more common in men. Here is the latest research on sexual dimorphism in neurodegeneration

Protein Localization in Disease & Therapy

Localization of proteins is critical for ensuring the correct location for physiological functioning. If an error occurs, diseases such as cardiovascular, neurodegenerative disorders and cancers can present. Therapies are being explored to target this mislocalization. Here is the latest research on protein localization in disease and therapy.

Genetic Screens in Bacteria

Genetic screens can provide important information on gene function as well as the molecular events that underlie a biological process or pathway. Here is the latest research on genetic screens in bacteria.

Head And Neck Squamous Cell Carcinoma

Squamous cell carcinomas account for >90% of all tumors in the head and neck region. Head and neck squamous cell carcinoma incidence has increased dramatically recently with little improvement in patient outcomes. Here is the latest research on this aggressive malignancy.

Artificial Intelligence in Cardiac Imaging

Artificial intelligence (ai) techniques are increasingly applied to cardiovascular (cv) medicine in cardiac imaging analysis. Here is the latest research.