New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells

Area of Science:

• Oncology
• Pharmacology
• Computational Biology

Background:

• Drug resistance remains a significant challenge in cancer therapy.
• Heat shock protein 27 (HSP27/HSPB1) is implicated in promoting cancer cell survival and resistance to chemotherapy.
• HSP27 overexpression affects apoptosis, DNA repair, and metastasis, contributing to treatment failure.

Purpose of the Study:

• To identify novel inhibitors of HSP27 using a computational drug repositioning strategy.
• To validate the efficacy of identified compounds in inhibiting HSP27 activity and overcoming drug resistance.

Main Methods:

• A computational approach leveraging structural similarity between HSP27 binding sites and viral thymidine kinase was employed.
• Lead compounds were generated based on this predicted similarity.
• Experimental validation included assessing compound binding to HSP27, inhibition of chaperone activity, and efficacy in cellular drug resistance assays.

Main Results:

• Six lead compounds targeting HSP27 were identified and experimentally validated.
• These compounds demonstrated binding to HSP27 and successfully down-regulated its chaperone activity.
• All six compounds effectively inhibited the development of drug resistance in cellular models.
• Chlorpromazine, an existing antipsychotic, was among the identified leads and showed a positive impact on breast cancer survival in human studies.

Conclusions:

• Novel HSP27 inhibitors were discovered through a computational drug repositioning approach.
• These inhibitors show promise in combating cancer drug resistance.
• The study highlights the potential of computational drug repositioning for identifying new therapeutic agents.