2026 Volume 41 Issue 2 Pages 126-133
Hematopoietic prostaglandin D synthase (HPGDS) is a key enzyme responsible for the biosynthesis of PGD2 and has been implicated in the pathogenesis of severe asthma, atopic dermatitis, and Duchenne muscular dystrophy (DMD). Although small-molecule HPGDS inhibitors have been developed, their clinical efficacy has been limited in certain disease settings, potentially due to insufficient and non-sustained suppression of PGD2 production. To overcome these limitations, we developed a proteolysis-targeting chimera (PROTAC) designed to induce selective degradation of HPGDS via the ubiquitin–proteasome system. Using high-resolution X-ray crystal structural information of HPGDS, we rationally designed a highly specific HPGDS-binding ligand and conjugated it to a E3 ligase, Cereblon (CRBN)-recruiting ligand through an optimized linker. Structure-guided modeling and in silico ternary complex simulations enabled refinement of the spatial orientation between HPGDS and CRBN, resulting in PROTAC-HPGDS compounds exhibiting remarkably potent degradation activity in the picomolar range. These degraders achieved efficient and sustained suppression of HPGDS protein levels, suggesting a potential advantage over conventional enzymatic inhibition. In addition, we established a rapid and time-resolved evaluation platform for HPGDS degradation by constructing a fluorescent protein–fused HPGDS expression system. This approach allows real-time monitoring of degradation kinetics without reliance on conventional Western blot analysis, thereby significantly improving throughput and quantitative assessment of PROTAC activity. The fluorescence-based system was validated both in cultured cells and in preliminary in vivo imaging experiments. Collectively, this study demonstrates an integrated drug discovery strategy that combines structural biology, rational ligand design, and targeted protein degradation technology. The development of PROTAC-HPGDS and its associated screening platform provides a promising therapeutic approach for diseases driven by excessive PGD2 production and supports the clinical potential of degradation-based modalities for inflammatory and neuromuscular disorders.
