2. Academic Validation
  3. Pharmacologic interrogation of USP28 cellular function in p53 signaling

Pharmacologic interrogation of USP28 cellular function in p53 signaling

  • Cell Chem Biol. 2025 Sep 18;32(9):1166-1182.e27. doi: 10.1016/j.chembiol.2025.08.002.
Ariana S Bratt 1,  Susan Kilgas 2,  Maria I Tarazona Guzman 1,  Robert S Magin 1,  Isabella Jaen Maisonet 1,  Cara A Starnbach 1,  Wei Pin Teh 1,  Anthony C Varca 1,  Bin Hu 1,  Esteban Tarazona Guzman 1,  Hyuk-Soo Seo 3,  Sirano Dhe-Paganon 3,  Nicholas M Girardi 1,  Guillaume Adelmant 4,  Jarrod A Marto 4,  Dipanjan Chowdhury 2,  Sara J Buhrlage 5
Affiliations

Affiliations

  • 1 Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Department of Oncologic Pathology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
  • 5 Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: saraj_buhrlage@dfci.harvard.edu.
PMID: 40902594 DOI: 10.1016/j.chembiol.2025.08.002
Abstract

Deubiquitinating Enzymes (DUBs) are crucial regulators of ubiquitin signaling and protein degradation that remain incompletely understood in part due to the lack of high-quality chemical probes. To address this challenge, we developed CAS-010, a low nanomolar, ubiquitin-competitive inhibitor of USP28 that demonstrates preferential activity against USP28 over Other DUBs, while also exhibiting some activity against the closely related USP25. We rationalized our SAR trends and observed selectivity using a crystal structure of USP28 in complex with an inhibitor. We validated on-target effects of CAS-010 on the negative regulation of p53 transactivation in the wild-type setting. We demonstrated that CAS-010 disrupts the 53BP1-USP28 interaction, and more broadly showed that USP28 catalytic activity contributes to this key interaction. Taken together, CAS-010 and the accompanying negative control compound WPT-086 and inhibitor-resistant mutant provide well-validated tools for further characterizing the role of USP28 in p53-mediated effect on cell cycle control and cell fate.

Keywords

53BP1; DUB; USP28; chemical probe; crystal structure; deubiquitinating enzyme; p53; p53 transcriptional regulation.

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