Targeting HSP70 protein-protein interactions for cancer precision Therapy: Mechanisms, structures, and inhibitor
Long-Tian Li1, Yue-Ying Yang1, Shi-Chen Zhang1
1Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, 110004, PR China.
Abstract:
Dysregulated protein homeostasis and aberrant signaling pathways are established hallmarks of cancer. Among key molecular players, heat shock protein 70 (HSP70) exerts critical oncogenic functions by forming stable protein-protein interactions (PPIs) with co-chaperones and client proteins, thereby sustaining malignant signaling, suppressing apoptosis, and promoting drug resistance. However, conventional ATPase inhibitors targeting HSP70 face clinical limitations, including target conservation, systemic toxicity, and induction of the heat shock response. Inhibitors targeting HSP70 PPIs demonstrate superior selectivity, reduced toxicity, and enhanced resistance. This review systematically examines the mechanisms through which major HSP70-mediated PPIs drive tumor progression and treatment resistance. Furthermore, we provide structural insights into druggable PPI interfaces localized to the HSP70 nucleotide-binding domain (NBD) and C-terminal TPR-recognition motif, critically evaluating recent advances in the development of small-molecule and peptide-based PPI inhibitors. Together, these analyses offer new perspectives for advancing precision cancer therapeutics.
Insights
Heat shock protein 70 (HSP70) drives cancer by protein-protein interactions (PPIs). Targeting these HSP70 PPIs, rather than ATPase activity, offers a more selective and less toxic approach for cancer therapeutics.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cancer is characterized by disrupted protein homeostasis and aberrant signaling.
- Heat shock protein 70 (HSP70) is a key oncogenic protein, promoting tumor progression and drug resistance through protein-protein interactions (PPIs).
- Conventional HSP70 ATPase inhibitors have clinical limitations, including toxicity and lack of specificity.
Purpose of the Study:
- To review the mechanisms by which HSP70-mediated PPIs contribute to cancer progression and treatment resistance.
- To explore structural insights into druggable PPI interfaces within HSP70.
- To evaluate recent advancements in HSP70 PPI inhibitors for cancer therapy.
Main Methods:
- Systematic review of literature on HSP70 functions in cancer.
- Analysis of structural data for HSP70 PPI interfaces.
- Critical evaluation of small-molecule and peptide-based HSP70 PPI inhibitors.
Main Results:
- HSP70's oncogenic functions are mediated by stable PPIs with co-chaperones and client proteins.
- HSP70 PPI inhibitors show improved selectivity, reduced toxicity, and enhanced efficacy compared to ATPase inhibitors.
- Druggable PPI interfaces are identified in the HSP70 nucleotide-binding domain (NBD) and C-terminal TPR-recognition motif.
Conclusions:
- Targeting HSP70-mediated PPIs represents a promising strategy for precision cancer therapeutics.
- Development of novel small-molecule and peptide inhibitors targeting these PPIs is advancing.
- This approach offers potential for overcoming limitations of current cancer treatments.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:26Protein Networks
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
02:04Protein-protein Interfaces