Discovery of Proteolysis-targeting chimeras (PROTACs)

Proteolysis Targeting Chimera (PROTAC) is a bivalent molecule consisting of a POI binder, an E3 ligase binder, and a linker tethering the two binders. Transferring an inhibitor and known E3 ligase binders (most commonly used ones are CRBN and VHL binders) with suitable linkers has been very popular in the past couple of years and yielded several clinical PROTAC programs. The efficacy against mutations, lower dosage and long-lasting effect highlights the PROTAC advantages over direct inhibitors.

POI Ligand Identification

The DEL compounds are covalently linked to DNA tags and share similar structural features with targeted protein degradation chimeric molecules. DEL screening is an affinity-based approach capable of identifying small molecular ligands for both functional and non-functional proteins. The binding affinities of these molecules typically range from nM to μM. DEL screening serves as a highly efficient and cost-effective pathway for ligand discovery. HitGen Inc has successfully screened 41 target types, including protein-protein interactions, ligases, transcription factors, and other challenging categories of targets.

Linker Optimization

Substantial efforts in bifunctional protein degrader research focus on linker optimization. The pursuit of molecules achieving optimal degradation efficacy faces multiple uncertainties – including ligand selection, linker attachment sites, and variations in linker types/lengths – making this optimization process inherently time-consuming. To streamline development, HitGen Inc has developed a ternary complex-based PROTAC-DEL screening technology and a high-throughput PROTAC synthesis platform leveraging diverse linker repositories. These integrated approaches significantly accelerate PROTAC identification and optimization cycles.