Rational Chemical Design of Molecular Glue Degraders

Targeted protein
degradation with molecular glue degraders has
arisen as a powerful therapeutic modality for eliminating classically
undruggable disease-causing proteins through proteasome-mediated degradation.
However, we currently lack rational chemical design principles for
converting protein-targeting ligands into molecular glue degraders.
To overcome this challenge, we sought to identify a transposable chemical
handle that would convert protein-targeting ligands into molecular
degraders of their corresponding targets. Using the CDK4/6 inhibitor
ribociclib as a prototype, we identified a covalent handle that, when
appended to the exit vector of ribociclib, induced the proteasome-mediated
degradation of CDK4 in cancer cells. Further modification of our initial
covalent scaffold led to an improved CDK4 degrader with the development
of a but-2-ene-1,4-dione (“fumarate”) handle that showed
improved interactions with RNF126. Subsequent chemoproteomic profiling
revealed interactions of the CDK4 degrader and the optimized fumarate
handle with RNF126 as well as additional RING-family E3 ligases. We
then transplanted this covalent handle onto a diverse set of protein-targeting
ligands to induce the degradation of BRD4, BCR-ABL and c-ABL, PDE5,
AR and AR-V7, BTK, LRRK2, HDAC1/3, and SMARCA2/4. Our study undercovers
a design strategy for converting protein-targeting ligands into covalent
molecular glue degraders.