Revealing GRP75-Mediated Mitochondrial Stability That Promotes Breast Cancer Survival through Subcellular Anchoring of 70 kDa Heat Shock Protein Inhibitors
The 70 kDa heat shock protein (HSP70) isoforms play distinct roles in cancer, but their structural similarity limits isoform-specific inhibition. Here, we modified nonselective HSP70 inhibitor <b>S1g-10</b> via a subcellular anchoring strategy to generate compounds <b>5</b> and <b>8</b>, which selectively target mitochondrial-localized GRP75 and ER-localized GRP78, respectively. Both compounds modulated their intended targets in vivo. Additionally, GRP75, but not GRP78, was identified as a key regulator of mitochondrial membrane stability in breast cancer cells and maintains the stemness of breast cancer stem cells (BCSCs). Compared with normal cells, compound <b>5</b> exhibited selective toxicity against breast cancer cells and effectively suppressed the properties of BCSCs. This study provides novel chemical probes for studying specific isoforms of HSP70 and introduces a strategy to develop GRP75-targeted therapeutics for breast cancer.
Authors
- Yang Song (ORCID: https://orcid.org/0000-0001-7716-9216)
- Fangkui Yin
- Zhiyuan Hu (ORCID: https://orcid.org/0000-0003-2212-0268)
- Maojun Jiang
- H. M. Lun
- Ziqian Wang (ORCID: https://orcid.org/0000-0002-0479-9871)
- Zhichao Zhang (ORCID: https://orcid.org/0000-0002-2774-2384)
- Zihan Wang (ORCID: https://orcid.org/0000-0001-6601-2520)
- Yitong Li (ORCID: https://orcid.org/0000-0003-4932-6987)
- Hong Zhang (ORCID: https://orcid.org/0000-0001-9790-0555)
- Siyao Wang (ORCID: https://orcid.org/0000-0003-4362-1344)
- Ke Wang
- Yi Teng (ORCID: https://orcid.org/0009-0000-4968-3787)
- Zhe-Ming Wang (ORCID: https://orcid.org/0000-0002-1986-4357)
- Ting Song (ORCID: https://orcid.org/0000-0002-5952-180X)
- Siting Feng
- Zixuan Yang (ORCID: https://orcid.org/0009-0003-0008-7863)
- Xiuwen Fan
- Yanxin Zhang
Institutions
- Dalian Medical University (CN)
- Dalian University of Technology (CN)
- Dalian Municipal Central Hospital (CN)
- First Affiliated Hospital of Dalian Medical University (CN)
- Affiliated Zhongshan Hospital of Dalian University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-09-12
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01279
- Citations
- 1
- Primary Topic
- Heat shock proteins research
- Type
- article
- Field-Weighted Citation Impact
- 0.81