Cereblon Modulators Target ZBTB16 and Its Oncogenic Fusion Partners for Degradation via Distinct Structural Degrons

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Targeted protein degradation is a promising therapeutic strategy to expand the range of druggable proteins.
• Molecular glues targeting the Cereblon E3 ligase complex represent a key approach in targeted protein degradation.

Purpose of the Study:

• To identify new substrates for Cereblon E3 ligase.
• To develop novel Cereblon modulators for targeted protein degradation.
• To explore the therapeutic potential of targeting ZBTB16 in acute promyelocytic leukemia.

Main Methods:

• Identification of ZBTB16 as a neosubstrate of Cereblon.
• Development and characterization of Cereblon modulators CC-3060 and CC-647.
• Analysis of ZBTB16 degradation pathways and structural degrons.
• Investigation of ZBTB16-RARα and RARα-ZBTB16 fusion proteins.

Main Results:

• ZBTB16 was identified as a novel Cereblon neosubstrate.
• CC-3060 and CC-647 were found to induce ZBTB16 degradation via distinct structural degrons.
• ZBTB16-RARα and RARα-ZBTB16 fusion proteins, implicated in acute promyelocytic leukemia, were also susceptible to degradation by Cereblon modulators.
• These findings highlight a potential therapeutic strategy for acute promyelocytic leukemia.

Conclusions:

• ZBTB16 is a novel Cereblon neosubstrate targeted by molecular glues CC-3060 and CC-647.
• Targeting ZBTB16 degradation offers a potential therapeutic avenue for acute promyelocytic leukemia driven by ZBTB16/RARA rearrangements.