Design and evaluation of an HSP70-targeting PROTAC in synergy with an HSF1 inhibitor for enhanced antitumor activity

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Heat Shock Protein (HSP) 70 is a promising anti-tumor target.
• Developing effective HSP70 inhibitors faces challenges, including resistance via HSP upregulation.

Purpose of the Study:

• To develop novel Proteolysis-targeting Chimeras (PROTACs) for selective HSP70 degradation.
• To enhance anti-tumor efficacy by combining PROTACs with a heat shock factor 1 (HSF1) inhibitor.

Main Methods:

• Designed non-ATP site PROTACs engaging the E3 ubiquitin ligase CRBN to degrade HSP70.
• Investigated combination therapy with an HSF1 inhibitor (DTHIB) to overcome HSP70 upregulation.
• Assessed synergistic and selective anti-tumor activity in cancer cell lines.

Main Results:

• PROTACs alone showed limited HSP70 degradation activity.
• Combination therapy with DTHIB markedly enhanced HSP70 degradation by disrupting the heat shock feedback loop.
• The combination strategy demonstrated synergistic and selective anti-tumor effects across various cancer cell lines.
• Compound C4 preferentially targeted cytosolic HSP70, circumventing compensatory upregulation.

Conclusions:

• Combination therapy of HSP70-targeting PROTACs with HSF1 inhibitors offers a promising strategy to overcome drug resistance.
• This approach enhances selective anti-tumor activity by effectively degrading HSP70.
• Novel PROTACs, like C4, can overcome compensatory HSP70 upregulation, improving therapeutic potential.