Targeted protein degradation of HSP90 and associated proteins for cancer therapy via PROTACs and beyond

In recent years, heat shock protein 90 (HSP90), a widely expressed molecular chaperone, has emerged as a promising anticancer target due to its crucial role in stabilizing and regulating the functions of numerous client proteins involved in various essential cellular processes, including protein folding, signalling pathways, and activation of tumor-associated proteins. Despite extensive developments, only one HSP90 inhibitor has gained approval, reflecting the complexity of the HSP90 chaperone machinery, associated side effects, and emergence of resistance mechanisms. To overcome these limitations, researchers have focused their attention on developing targeted protein degraders (TPDs), a revolutionary therapeutic approach that selectively eliminates specific dysregulated target proteins. TPDs exploit cellular degradation pathways, including the ubiquitin-proteasome system (UPS), lysosomal pathways, and autophagy to achieve precise protein degradation. Among these strategies, proteolysis-targeting chimeras (PROTACs) as well as HEMTAC/HIM-PROTACs have emerged as prominent UPS-based technologies. PROTACs link targets to E3 ligases for proteasomal removal, where HEMTACs exploit HSP90 to drive client ubiquitination, thereby offering significant potential for cancer therapeutics. Given HSP90's role in tumor progression and considering the potential of TPDs, researchers have designed and developed various HSP90-targeting PROTACs and HEMTAC/HIM-PROTACs, which exhibits remarkable efficacy, selectivity, antiproliferative potency, and the ability to overcome drug resistance. This review highlights the structural and biological functions of HSP90, delineates the mechanistic principles underlying its degradation, and summarizes the structure-activity relationships (SARs) inlcuding the synthetic strategies employed across different HSP90-directed TPD modalities. Furthermore, the challenges and opportunities associated with the utilization of HSP90 and their client proteins in developing TPDs-based therapeutics to tackle the unmet clinical needs in cancer have been discussed.