PROTACS AND MOLECULAR GLUES: TARGETED PROTEIN DEGRADATION AS A NEXT-GENERATION PHARMACOLOGICAL STRATEGY

Targeted protein degradation has emerged as a transformative pharmacological approach that exploits the ubiquitin-proteasome system to eliminate disease-relevant proteins rather than merely inhibiting their function. Two principal classes of degraders have advanced rapidly: proteolysis-targeting chimeras (PROTACs) and molecular glues. PROTACs are heterobifunctional molecules that simultaneously bind a target protein and an E3 ubiquitin ligase, inducing proximity-dependent ubiquitination and subsequent proteasomal degradation. Molecular glues, by contrast, are small molecules that modify the surface of an E3 ligase or target protein to promote or enhance protein–protein interactions leading to degradation. This review critically examines the design, mechanism, and clinical progress of PROTACs and molecular glues through early 2024. Key PROTAC programs targeting the estrogen receptor, androgen receptor, Bruton’s tyrosine kinase, and other oncogenic drivers have entered clinical trials, with early data demonstrating degradation and preliminary efficacy. Molecular glues, exemplified by the immunomodulatory imide drugs thalidomide, lenalidomide, and pomalidomide, have validated the clinical potential of induced proximity, and next-generation glues targeting additional ligases and substrates are in development. Challenges include oral bioavailability, permeability, selectivity, acquired resistance, and the need for robust biomarkers of target engagement and degradation. Future directions include expanding the repertoire of E3 ligases, improving tissue selectivity, and applying degradation to previously undruggable proteins. Overall, targeted protein degradation represents a paradigm shift in drug discovery, with the potential to address therapeutic targets beyond the reach of conventional inhibitors.