AtomNet-Aided OTUD7B Inhibitor Discovery and Validation
Jianfeng Chen1,2, Derek L Bolhuis1,2, Christian Laggner3
1Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Abstract:
Protein deubiquitinases play critical pathophysiological roles in cancer. Among all deubiquitinases, an oncogenic function for OTUD7B has been established in genetic NSCLC murine models. However, few deubiquitinase inhibitors have been developed due to technical challenges. Here, we report a putative small molecule OTUD7B inhibitor obtained from an AI-aided screen of a 4 million compound library. We validated the effects of the OTUD7B inhibitor (7Bi) in reducing Akt-pS473 signals in multiple NSCLC and HEK293 cells by blocking OTUD7B-governed GβL deubiquitination in cells, as well as inhibiting OTUD7B-mediated cleavage of K11-linked di-ub in an in vitro enzyme assay. Furthermore, we report in leukemia cells, either genetic depletion or 7Bi-mediated pharmacological inhibition of OTUD7B reduces Akt-pS473 via inhibiting the OTUD7B/GβL signaling axis. Together, our study identifies the first putative OTUD7B inhibitor showing activities both in cells and in vitro, with promising applications as a therapeutic agent in treating cancer with OTUD7B overexpression.
Insights
Researchers identified a novel small molecule inhibitor (7Bi) targeting OTUD7B, a protein involved in cancer. This inhibitor shows promise for treating cancers like NSCLC and leukemia by reducing key signaling pathways.
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.
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