Emerging opportunities and challenges in small molecule development for non-HSP90 chaperones

Heat shock proteins (HSPs) are pivotal regulators of proteostasis, with their dysregulation implicated in cancer, neurodegeneration, and infectious diseases. Significant progress has been made in targeting HSP90, particularly in oncology, where inhibitors have demonstrated considerable therapeutic potential and validated HSP90 as a promising drug target. However, other HSP families remain relatively underexplored as drug targets despite their critical biological roles. This review systematically explores the development of small-molecule inhibitors against non-HSP90 family members (HSP110, HSP70, HSP60, HSP40, and HSP27), highlighting their therapeutic potential and unique mechanisms. Despite progress in targeting these non-HSP90 chaperones, key challenges persist. We aim to underscore the potential of non-HSP90 inhibitors, providing new prospects for future drug discovery through innovation in medicinal chemistry and structural biology.