Identification of OTUD7B Inhibitor 7Bi and Its Application in Reducing Growth of NSCLC and Leukemia Cells

Background

OTUD7B is a deubiquitinase that regulates inflammation, T-cell activation, and cell signaling pathways that promote tumor progression in various cancers. However, its function in cancer remains largely unknown, and a few deubiquitinase inhibitors have been developed due to technical challenges.

Technology Overview

UNC researchers discovered a series of compounds that selectively inhibit the catalytic activity of OTUD7B deubiquitinase using an AI-aided screen of a 4 million compound library. The lead compound, 7Bi, demonstrated anti-oncogenic activity and inhibited cell growth in multiple non-small cell lung cancer & leukemia cell lines via selectively blocking OTUD7B-induced deubiquitination. In the non-small cell lung cancer (NSCLC) model, the 7Bi treatment increased ubiquitination K63-linked ubiquitination of GβL, which attenuated mTORC2 kinase complex formation, thus weakening Akt activation in facilitating cell proliferation and survival. Furthermore, the study discovered that OTUD7B also governs various leukemia cell proliferation, and 7Bi treatment effectively reduces cell growth in vitro. 7Bi is the first putative OTUD7B inhibitor in reducing cellular signaling pathways important in cancer growth, thus showing a promise to use OTUD7B inhibitors in treating cancers with OTUD7B over-expression, including triple-negative breast cancer, non-small cell lung cancer, and leukemia.

Applications

• Cancer therapy
• Small molecule
• Deubiquitinase inhibitor
• Non-small cell lung cancer (NSCLC)
• Leukemia
• Triple‑negative breast cancer (TNBC)