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

ABSTRACT: Heat shock protein (HSP) 70 represents a clinically promising anti-tumor target, yet the development of effective inhibitors faces numerous technical challenges. To address this, we developed novel non-ATP site Proteolysis-targeting Chimeras (PROTACs) that selectively degrade HSP70 by engaging the E3 ubiquitin ligase CRBN. However, the PROTACs exhibited limited degradation activity, potentially due to heat shock response-mediated HSP70 upregulation. To circumvent this resistance mechanism, we explored combination therapy with the heat shock factor 1 (HSF1) inhibitor DTHIB to disrupt the heat shock feedback loop, markedly enhancing HSP70 degradation. The combination strategy showed synergistic and selective anti-tumor activity across a panel of cancer cell lines. This success relied on the

SUBMITTER: Huang WH 

PROVIDER: S-EPMC12626032 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature