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In cellular biology, Heat Shock Protein 90 (Hsp90) plays a pivotal role in coordinating several processes essential or cellular survival, cell signaling and other processes. This analysis explores the complex structure, biological significance, and regulatory mechanisms clarifying its essential function in preserving cellular homeostasis and its relevance in a range of illnesses, such as cancer, neurological conditions, infectious diseases, cardiovascular conditions, and autoimmune diseases. Hsp90 is a prominent target for cancer treatment. The current manuscript involved the recent progress in the synthesis and development of Hsp90 inhibitor for the treatment of cancer. In this manuscript, the authors have compiled the Hsp90 inhibitors containing various heterocyclic rings such as Benzothiazone, Benzamide, Isoxazole, Pyrimidinone, Imidazole, Pyrimidine, Isatin, Quinazoline and Pyrazole etc. In this review, the authors incorporate the anticancer activity, Structure-Activity Relationship (SAR), Molecular Docking studies and Biological Evaluation of recently synthesized Hsp90 inhibitors. The authors have also added the clinical trial status of Hsp90 inhibitors and their potential use in cancer therapy. Overall, this review highlights the recent advancements in the field of Hsp90 inhibitor from 2020 to present. This review provides medicinal chemists with comprehensive insights into the development of Hsp90 inhibitors by guiding future research and drug discovery efforts in cancer.
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http://dx.doi.org/10.1007/s11030-025-11314-3 | DOI Listing |
Bioorg Med Chem Lett
September 2025
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, United States. Electronic address:
The mitochondrial Hsp90 isoform, Tumor Necrosis Factor Receptor Associated Protein 1 (TRAP1), is central to the pathogenesis of disease states that include cancer, ischemic retinopathy, and diabetic kidney disease among others. TRAP1 contributes to these diseases through the regulation of mitochondrial metabolism, apoptosis, oxidative stress, cell signaling and angiogenesis through interactions with client proteins. Numerous TRAP1-selective inhibitors have been developed to limit the toxicities associated with Hsp90 pan-inhibition, while leveraging the therapeutic benefits of TRAP1 inhibition.
View Article and Find Full Text PDFEur J Med Chem
August 2025
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: leiwang.9
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.
View Article and Find Full Text PDFBioorg Med Chem
August 2025
Department of Chemistry, Duke University, Durham, NC, USA; Department of Molecular Genetics & Microbiology, Duke Medical School, Durham, NC, USA. Electronic address:
The molecular chaperone heat shock protein 90 (Hsp90) has an important role in maintaining proteostasis in Plasmodium parasites, the causative agents of malaria, and is of interest as a potential antimalarial drug target. Inhibitors targeting its well-characterized N-terminal ATP-binding site are lethal, but the development of high-affinity binders with selectivity for the Plasmodium over the human homolog has been challenging given the high conservation of this domain. A binding site in the less conserved Hsp90 C-terminus has been reported to interact with nucleotides and inhibitors in other eukaryotic systems, which could offer an alternative route for antimalarial design.
View Article and Find Full Text PDFJ Zhejiang Univ Sci B
August 2025
Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
Cancer is characterized by abnormal cell proliferation. Cyclins and cyclin-dependent kinases (CDKs) have been recognized as essential regulators of the intricate cell cycle, orchestrating DNA replication and transcription, RNA splicing, and protein synthesis. Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers, rendering cyclins and CDKs attractive therapeutic targets.
View Article and Find Full Text PDFEur J Pharmacol
August 2025
The Second Department of Thoracic Medical Oncology, Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. Electronic address:
Resistance to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with epidermal growth factor (EGF) receptor mutations severely limits the efficacy of cancer therapies. Therefore, there is an urgent clinical demand to find novel therapeutic strategies that can produce durable responses for such patients. EGF receptor-L858R is a common activating mutation and T790M/C797S can account for acquired resistance to EGF receptor-TKI like gefitinib.
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