Small molecules targeting HSP70 and therapeutic potentials

Heat shock protein 70 (HSP70), a crucial member of molecular chaperones, plays a pivotal role in maintaining cellular homeostasis and protecting cells from proteotoxic stress. Its strong pathophysiological associations with various malignancies, neurodegenerative disorders, cardiovascular diseases, and metabolic syndromes, establishing HSP70 as a promising therapeutic target. However, the clinical development of HSP70 inhibitors remains in its infancy, with only two small molecule inhibitors having entered to clinical trials. This limited clinical progress underscores the need for further optimization of current candidates and the development of novel HSP70-targeted inhibitors. This review summarizes the development of HSP70 inhibitors into three distinct chemical strategies: (1) pan-HSP70 inhibitors that target the conserved ATPase domain shared across isoforms; (2) isoform-selective inhibitors that address specific HSP70 family members; and (3) protein-protein interaction inhibitors that disrupt functional chaperone complexes. This review has systematically linked the structural analysis of HSP70 (including its structure and co-chaperone networks), disease-associated signaling pathways, and pathological roles to establish a classification framework based on its four major subtypes (HSP70i, HSC70, GRP78, and GRP75).