2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Androgen Receptor (AR) Antagonist-Heat Shock Protein 90 (Hsp90) Inhibitor Conjugates for Targeted Therapy of Castration-Resistant Prostate Cancer

Design, Synthesis, and Biological Evaluation of Androgen Receptor (AR) Antagonist-Heat Shock Protein 90 (Hsp90) Inhibitor Conjugates for Targeted Therapy of Castration-Resistant Prostate Cancer

  • J Med Chem. 2023 Apr 13;66(7):4784-4801. doi: 10.1021/acs.jmedchem.2c01970.
Siqi Zhang 1 2,  Xiaolei Meng 1,  Sai Zhang 1 2,  Baohu Li 1,  Wencong Jin 1,  Chengwei Zhang 1,  Zhaojuan Liu 1,  Xiaolin Hu 1,  Ling Ge 1,  Zhonghao Yu 1,  Zhuoyue Li 1 2,  Shumin Ma 1 2,  Xiao Wang 1 2,  Liming Li 1 3,  Chong Qin 1 2 3
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China.
  • 2 Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China.
  • 3 Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao, Shandong 266137, China.
PMID: 36960664 DOI: 10.1021/acs.jmedchem.2c01970
Abstract

Androgen deprivation in cases of castration-resistant prostate Cancer (CRPC) leads to adverse effects, including loss of muscle and bone mass and gain of subcutaneous fat. The tumor-specific suppression of Androgen Receptor (AR) signaling, while not global, may reduce side effects. We present a class of small-molecular conjugates consisting of an AR antagonist linked to a heat shock protein 90 (HSP90) inhibitor. We demonstrate that the high accumulation of HSP90 on the surface of CRPC cells allows uptake of conjugates and increases the enrichment of drugs in the tumor cells. After penetrating prostate Cancer cells, the conjugates not only inhibit AR function by the antagonist component but also bind to HSP90 and suppress the AR protein level. Compared to AR antagonists, these conjugates showed improved tumor-targeting ability and enhanced potency against Enzalutamide-resistant 22Rv1 cells.

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