{
  "abstract": "Background Ubiquitin-specific peptidase 7 (USP7) is a deubiquitinating enzyme that removes ubiquitin from specific protein substrates to modify their degradation rates thereby regulating crucial cellular processes integral to cancer. Conspicuously, overexpression of USP7 is strongly associated with the progression and poor prognosis in various cancers. Therefore, the design of potent and selective USP7 inhibitors poses an attractive therapeutic approach. The mechanism of action of USP7 inhibitors in cancer cells relies on MDM2 depletion and the restoration of p53.Methods In this study, we present OAT-4828, a novel and highly potent USP7-selective lead compound with a pharmacokinetic profile suitable for an oral administration. In in vivo models of melanoma and colon cancers, we determine the antitumor activity of OAT-4828, revealing its significant influence on various immune cell populations by flow cytometry.Results We provide evidence that OAT-4828 alters the tumor microenvironment, affecting immune cells including T cells, macrophages, and dendritic cells. As a result, OAT-4828 enhances antitumor functions, specifically improves T-cell activity, manifested by increased cytotoxicity, which is crucial for the effectiveness of OAT-4828 in vivo. Moreover, OAT-4828 changes the phenotype of macrophages and dendritic cells by decreasing the level of immunosuppressive proteins, such as programmed death-ligand 1. Translational results from the human co-culture system revealed the unexpected anti-angiogenic effect of the USP7 inhibitor, which was not observed when compared with an MDM2 inhibitor.Conclusions Overall, OAT-4828 demonstrates significant anticancer efficacy in melanoma and colon cancer models by activating the immune system, suggesting that USP7 may function as a checkpoint contributing to immunosuppression in cancer.",
  "authors": [
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland",
        "Laboratory of Cellular and Genetic Therapies, Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland"
      ],
      "name": "Angelika Muchowicz"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Katarzyna M Głuchowska"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Marcin M Grzybowski"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Małgorzata Szostakowska-Rodzos"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Tomasz Rejczak"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Agnieszka Belczyk-Ciesielska"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland",
        "Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Lesser Poland Voivodeship, Poland"
      ],
      "name": "Mieszko M Wilk"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Agnieszka Kikulska"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Patrycja Marzeta-Assas"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Agnieszka Zagozdzon"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Paulina Pomper"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Katarzyna Piwowar"
    },
    {
      "affiliations": [
        "Laboratory of Cellular and Genetic Therapies, Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland",
        "Doctoral School, Medical University of Warsaw, Warsaw, Poland"
      ],
      "name": "Marta Bryla"
    },
    {
      "affiliations": [
        "Laboratory of Cellular and Genetic Therapies, Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland",
        "Doctoral School, Medical University of Warsaw, Warsaw, Poland"
      ],
      "name": "Alicja Wojciechowska"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Jacek Chrzanowski"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Julita Nowicka"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Anna Gzik"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Lukasz Joachimiak"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Robert Koralewski"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Roman Błaszczyk"
    },
    {
      "affiliations": [
        "Laboratory of Cellular and Genetic Therapies, Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland",
        "Department of Bioinformatics, Polish Academy of Sciences, Warszawa, Poland"
      ],
      "name": "Radoslaw Zagozdzon"
    },
    {
      "affiliations": [
        "Molecure SA, Warsaw, Poland"
      ],
      "name": "Zbigniew Zasłona"
    }
  ],
  "title": "Therapeutic inhibition of USP7 promotes antitumor immune responses",
  "uid": "25223002-4ac0-5717-8ba2-e6bb35dd34d5"
}