Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications

Proteolysis-targeting
chimeras (PROTACs), heterobifunctional compounds
that consist of protein-targeting ligands linked to an E3 ligase recruiter,
have arisen as a powerful therapeutic modality for targeted protein
degradation (TPD). Despite the popularity of TPD approaches in drug
discovery, only a small number of E3 ligase recruiters are available
for the >600 E3 ligases that exist in human cells. Here, we have
discovered
a cysteine-reactive covalent ligand, EN106, that targets FEM1B, an
E3 ligase recently discovered as the critical component of the cellular
response to reductive stress. By targeting C186 in FEM1B, EN106 disrupts
recognition of the key reductive stress substrate of FEM1B, FNIP1.
We further establish that EN106 can be used as a covalent recruiter
for FEM1B in TPD applications by demonstrating that a PROTAC linking
EN106 to the BET bromodomain inhibitor JQ1 or the kinase inhibitor
dasatinib leads to the degradation of BRD4 and BCR-ABL, respectively.
Our study showcases a covalent ligand that targets a natural E3 ligase–substrate
binding site and highlights the utility of covalent ligand screening
in expanding the arsenal of E3 ligase recruiters suitable for TPD
applications.