2. Academic Validation
  3. Ubiquitin-specific protease 7 inhibitors reveal a differentiated mechanism of p53-driven anti-cancer activity

Ubiquitin-specific protease 7 inhibitors reveal a differentiated mechanism of p53-driven anti-cancer activity

  • iScience. 2024 Apr 9;27(5):109693. doi: 10.1016/j.isci.2024.109693.
Alan S Futran 1,  Tao Lu 2,  Katherine Amberg-Johnson 1,  Jiayi Xu 1,  Xiaoxiao Yang 2,  Saidi He 2,  Sarah Boyce 1,  Jeffrey A Bell 1,  Robert Pelletier 1,  Takao Suzuki 2,  Xianhai Huang 1,  Heng Qian 2,  Liping Fang 2,  Li Xing 2,  Zhaowu Xu 2,  Stephen E Kurtz 3 4,  Jeffrey W Tyner 3 5,  Wayne Tang 1,  Tao Guo 2,  Karen Akinsanya 1,  David Madge 2,  Kristian K Jensen 1
Affiliations

Affiliations

  • 1 Schrödinger, 1540 Broadway 24th Floor, New York, NY, USA.
  • 2 WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 3 Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • 4 Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA.
  • 5 Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
PMID: 38689642 DOI: 10.1016/j.isci.2024.109693
Abstract

The USP7 Deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and Epigenetics and has been implicated in Cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303. FX1-5303 was used as a chemical probe to study the USP7-mediated regulation of p53 signaling in cells. It demonstrates mechanistic differences compared to MDM2 antagonists, a related class of anti-tumor agents that act along the same pathway. FX1-5303 synergizes with the clinically approved BCL2 inhibitor venetoclax in acute myeloid leukemia (AML) cell lines and ex vivo patient samples and leads to strong tumor growth inhibition in in vivo mouse xenograft models of multiple myeloma and AML. This work introduces new USP7 inhibitors, differentiates their mechanism of action from MDM2 inhibition, and identifies specific opportunities for their use in the treatment of AML.

Keywords

Biochemistry; Cancer; Cell biology.

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