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

Targeted protein degradation with monovalent molecular
glue degraders
is a powerful therapeutic modality for eliminating disease causing
proteins. However, rational design of molecular glue degraders remains
challenging. In this study, we sought to identify a transplantable
and linker-less covalent handle that could be appended onto the exit
vector of various protein-targeting ligands to induce the degradation
of their respective targets. Using the BET family inhibitor JQ1 as
a testbed, we synthesized and screened a series of covalent JQ1 analogs
and identified a vinylsulfonyl piperazine handle that led to the potent
and selective degradation of BRD4 in cells. Through chemoproteomic
profiling, we identified DCAF16 as the E3 ligase responsible for BRD4
degradationan E3 ligase substrate receptor that has been previously
covalently targeted for molecular glue-based degradation of BRD4.
Interestingly, we demonstrated that this covalent handle can be transplanted
across a diverse array of protein-targeting ligands spanning many
different protein classes to induce the degradation of CDK4, the androgen
receptor, BTK, SMARCA2/4, and BCR-ABL/c-ABL. Our study reveals a DCAF16-based
covalent degradative and linker-less chemical handle that can be attached
to protein-targeting ligands to induce the degradation of several
different classes of protein targets.