Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Cullin-RING (CRL) E3 ubiquitin ligases are crucial for protein degradation and cellular processes, including cancer development.
• No small-molecule inhibitors targeting CRL catalytic activity have been reported previously.

Purpose of the Study:

• To identify and characterize small-molecule inhibitors of CRL E3 ligases.
• To evaluate the antitumor potential of identified inhibitors.

Main Methods:

• High-throughput screening and medicinal chemistry optimization were employed.
• Compounds 33-11 and KH-4-43 were identified and characterized for their inhibitory effects on CRL4.
• In vitro and in vivo studies using tumor cell lines and xenografts were conducted.

Main Results:

• Compounds 33-11 and KH-4-43 inhibit CRL4 by binding to its core catalytic complex.
• These inhibitors block CRL4-mediated ubiquitination and lead to the stabilization of the substrate CDT1.
• Cytotoxicity was observed in 36 tumor cell lines, and tumor growth was suppressed in mouse xenografts.
• Low expression of cullin4 proteins correlated with increased sensitivity to the compounds, suggesting a potential cancer vulnerability.

Conclusions:

• Novel small-molecule inhibitors (33-11 and KH-4-43) targeting CRL4 E3 ligases have been developed.
• These compounds demonstrate significant antitumor activity through CDT1 stabilization and apoptosis induction.
• The findings suggest that low E3 ligase abundance could represent a vulnerability in certain cancers.