DCAF16-Based Covalent Handle for the Rational Design of Monovalent Degraders

Area of Science:

• Chemical Biology
• Drug Discovery
• Molecular Medicine

Background:

• Targeted protein degradation using molecular glues is a promising therapeutic strategy.
• Designing effective molecular glue degraders remains a significant challenge in drug development.

Purpose of the Study:

• To identify a versatile, linker-less covalent handle for targeted protein degradation.
• To develop a transplantable chemical moiety that can be appended to various protein-targeting ligands.

Main Methods:

• Synthesis and screening of covalent analogs of the BET inhibitor JQ1.
• Chemoproteomic profiling to identify the responsible E3 ligase.
• Testing the transplantability of the covalent handle across diverse protein targets.

Main Results:

• A vinylsulfonyl piperazine handle was identified, inducing potent and selective BRD4 degradation.
• DCAF16 was identified as the E3 ligase mediating BRD4 degradation.
• The covalent handle was successfully applied to induce degradation of CDK4, androgen receptor, BTK, SMARCA2/4, and BCR-ABL/c-ABL.

Conclusions:

• A DCAF16-based, linker-less covalent handle enables targeted degradation of multiple protein classes.
• This approach offers a transplantable strategy for developing novel molecular glue degraders.
• The findings advance the field of targeted protein degradation for therapeutic applications.