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

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• The USP7 deubiquitinase enzyme plays a critical role in regulating key cellular processes, including cell cycle control, DNA repair, and epigenetic modifications.
• Dysregulation of USP7 activity has been linked to the progression of various cancers, making it a significant target for anti-cancer drug development.

Purpose of the Study:

• To discover and characterize novel, potent, and specific inhibitors of USP7.
• To investigate the USP7-mediated regulation of p53 signaling using FX1-5303 as a chemical probe.
• To explore the therapeutic potential of USP7 inhibitors in hematological malignancies, particularly acute myeloid leukemia (AML).

Main Methods:

• Discovery and profiling of USP7 inhibitors, exemplified by FX1-5303.
• Utilizing FX1-5303 as a chemical probe to elucidate USP7-dependent cellular pathways.
• Assessing the synergistic effects of FX1-5303 with venetoclax in AML cell lines and patient samples.
• Evaluating anti-tumor efficacy in in vivo mouse xenograft models of multiple myeloma and AML.

Main Results:

• Identification of FX1-5303 as a potent and specific USP7 inhibitor.
• Demonstration of distinct mechanistic differences between FX1-5303 and MDM2 antagonists.
• Significant synergy observed between FX1-5303 and venetoclax in AML models, both in vitro and ex vivo.
• Strong inhibition of tumor growth in vivo in models of multiple myeloma and AML.

Conclusions:

• Introduction of novel USP7 inhibitors with potential for cancer therapy.
• Clarification of the unique mechanism of action of USP7 inhibitors compared to MDM2 antagonists.
• Identification of a specific therapeutic opportunity for USP7 inhibitors in the treatment of AML, particularly in combination with BCL2 inhibitors.