2. Academic Validation
  3. Revealing GRP75-Mediated Mitochondrial Stability That Promotes Breast Cancer Survival through Subcellular Anchoring of 70 kDa Heat Shock Protein Inhibitors

Revealing GRP75-Mediated Mitochondrial Stability That Promotes Breast Cancer Survival through Subcellular Anchoring of 70 kDa Heat Shock Protein Inhibitors

  • J Med Chem. 2025 Sep 25;68(18):19169-19183. doi: 10.1021/acs.jmedchem.5c01279.
Maojun Jiang 1,  Yang Song 2,  Hong Zhang 1,  Fangkui Yin 1,  Zhiyuan Hu 3,  Zheming Wang 1,  Yitong Li 1,  Zihan Wang 1,  Yanxin Zhang 3,  Siyao Wang 1,  Teng Yi 1,  Ke Wang 4,  Siting Feng 5,  Zixuan Yang 6,  Xiuwen Fan 4,  Haoxin Lun 1,  Ting Song 4,  Ziqian Wang 4,  Zhichao Zhang 4
Affiliations

Affiliations

  • 1 Central Hospital of Dalian University of Technology, School of Chemistry, Dalian University of Technology, Dalian, Liaoning 116024, China.
  • 2 Central Hospital of Dalian University of Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
  • 3 School of Life Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
  • 4 Central Hospital of Dalian University of Technology, School of Pharmacy, Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning 116024, China.
  • 5 Department of Cardiology, First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, China.
  • 6 School of Pharmacy, ZhongShan College of Dalian Medical University, Dalian, Liaoning 116085, China.
PMID: 40938081 DOI: 10.1021/acs.jmedchem.5c01279
Abstract

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 S1g-10 via a subcellular anchoring strategy to generate compounds 5 and 8, 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 5 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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z