Design, synthesis, and biological evaluation of HSP70-mediated HEMTACs as novel androgen receptor degraders.

Targeted protein degradation (TPD) has emerged as an important therapeutic strategy for addressing challenging protein targets. While Proteolysis-Targeting Chimeras (PROTACs) are the leading TPD approach, their reliance on a limited set of E3 ligases poses challenges, including tissue-specific restrictions and the emergence of drug resistance. To address these limitations, we previously developed the HEMTAC (HEat shock protein-Mediated TArgeting Chimeras) platform, which recruits HSP90 to induce target protein degradation. Building on this concept, the current study expands the HEMTAC framework by integrating HSP70, a key molecular chaperone, to target the androgen receptor (AR). We designed and synthesized a series of novel HSP70-recruiting HEMTACs by linking an HSP70 ligand (a derivative of VER-155008) with an AR-binding ligand. Biological evaluation identified compound 39 as an active degrader that induced substantial AR degradation in LNCaP prostate cancer cells. This work supports the feasibility of recruiting HSP70 for TPD and provides a molecular tool for AR-degradation research, thereby expanding the TPD toolbox for future drug discovery.