AtomNet-Aided OTUD7B Inhibitor Discovery and Validation

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Protein deubiquitinases are crucial in cancer pathophysiology.
• OTUD7B has an oncogenic role in non-small cell lung cancer (NSCLC).
• Developing deubiquitinase inhibitors is challenging.

Purpose of the Study:

• To identify and validate a small molecule inhibitor for OTUD7B.
• To investigate the mechanism of action of the OTUD7B inhibitor.
• To explore the therapeutic potential of OTUD7B inhibition in cancer.

Main Methods:

• AI-aided screening of a large compound library.
• Cell-based assays in NSCLC and HEK293 cells.
• In vitro enzyme assays for deubiquitination activity.

Main Results:

• A novel small molecule inhibitor (7Bi) for OTUD7B was discovered.
• 7Bi reduces Akt-pS473 signaling by inhibiting OTUD7B-mediated GβL deubiquitination.
• 7Bi demonstrated efficacy in both cell-based and in vitro assays.
• OTUD7B inhibition also impacted leukemia cells via the OTUD7B/GβL axis.

Conclusions:

• This study presents the first putative OTUD7B inhibitor with demonstrated cellular and in vitro activity.
• The identified inhibitor (7Bi) has potential as a therapeutic agent for cancers overexpressing OTUD7B.
• Targeting the OTUD7B/GβL signaling axis offers a potential therapeutic strategy for cancer treatment.