Overcoming cancer drug resistance through small-molecule targeting of HSP90 and HSP70

Heat shock proteins (HSPs) play a critical role in cancer progression and drug resistance by stabilizing oncoproteins, enhancing DNA repair, and modulating apoptosis pathways. In particular, HSP90 and HSP70 have been implicated in maintaining the survival of drug-resistant cancer cells. Consequently, targeting HSPs holds promise in combating drug resistance in cancers. HSP inhibitors induce apoptosis in resistant cancer cells and act as potent chemosensitizers, enhancing the efficacy of chemotherapy, radiotherapy, and targeted therapies. However, despite promising preclinical data, no HSP inhibitors have been approved by the U.S. Food and Drug Administration (FDA) due to toxicity, limited treatment outcomes, or a lack of specificity. In this review, we attempted to provide a brief overview of small-molecule HSP inhibitors, including the medicinal chemistry of geldanamycin derivatives, resorcinol-based compounds, and purine-scaffold inhibitors. We summarized the recent advancements of HSP inhibitors, especially those in clinical trials, their mechanisms of action, and their combinations in overcoming multidrug resistance in cancers. Furthermore, we discussed the current challenges and proposed possible solutions.