Combinatorial Ubiquitination REal-time PROteolysis (CURE-PROs): A Modular Platform for Generating Reversible, Self-Assembling Bifunctional Targeted Degraders

Proteolysis-Targeting
Chimeras (PROTACs) are bifunctional
molecules
that bring a target protein and an E3 ubiquitin ligase into proximity
to append ubiquitin, thus directing target degradation. Although numerous
PROTACs have entered clinical trials, their development remains challenging,
and their large size can produce poor drug-like properties. To overcome
these limitations, we have modified our Coferon platform to generate
Combinatorial Ubiquitination REal-time PROteolysis (CURE-PROs). CURE-PROs
are small molecule degraders designed to self-assemble through reversible
bio-orthogonal linkers to form covalent heterodimers. By modifying
known ligands for Cereblon, MDM2, VHL, and BRD with complementary
phenylboronic acid and diol/catechol linkers, we have successfully
created CURE-PROs that direct degradation of BRD4 both in
vitro and in vivo. The combinatorial nature
of our platform significantly reduces synthesis time and effort to
identify the optimal linker length and E3 ligase partner to each target
and is readily amenable to screening for new targets.