2. Academic Validation
  3. Novel selective agents for the degradation of AR/AR-V7 to treat advanced prostate cancer

Novel selective agents for the degradation of AR/AR-V7 to treat advanced prostate cancer

  • Eur J Med Chem. 2024 May 5:271:116400. doi: 10.1016/j.ejmech.2024.116400.
Yifei Yang 1,  Guangyao Lv 2,  Ruijuan Xiu 3,  Huijie Yang 3,  Wenyan Wang 1,  Pengfei Yu 4,  Jianzhao Zhang 1,  Liang Ye 5,  Hongbo Wang 6,  Jingwei Tian 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong 264003, PR China.
  • 2 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China; Binzhou Medical University Hospital, Binzhou, Shandong, 256603, China.
  • 3 State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong 264003, PR China.
  • 4 State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong 264003, PR China; Department of Clinical Medicine, Binzhou Medical University, Yantai, 256603, China.
  • 5 State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong 264003, PR China; School of Public Health and Management, Binzhou Medical University, Yantai, China. Electronic address: [email protected].
  • 6 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong 264003, PR China. Electronic address: [email protected].
  • 7 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong 264003, PR China. Electronic address: [email protected].
PMID: 38626524 DOI: 10.1016/j.ejmech.2024.116400
Abstract

The Androgen Receptor AR antagonists, such as enzalutamide and apalutamide, are efficient therapeutics for the treatment of prostate Cancer (PCa). Even though they are effective at first, resistance to both drugs occurs frequently. Resistance is mainly driven by aberrations of the AR signaling pathway including AR gene amplification and the expression of AR splice variants (e.g. AR-V7). This highlights the urgent need for alternative therapeutic strategies. Here, a total of 24 compounds were synthesized and biologically evaluated to disclose compound 20i, exhibiting potent AR antagonistic activities (IC50 = 172.85 ± 21.33 nM), promising AR/AR-V7 protein degradation potency, and dual targeting site of probably AR (ligand-binding domain, LBD and N-terminal domain, NTD). It potently inhibits cell growth with IC50 values of 4.87 ± 0.52 and 2.07 ± 0.34 μM in the LNCaP and 22RV1 cell lines, respectively, and exhibited effective tumor growth inhibition (TGI = 50.9 %) in the 22RV1 xenograft study. These data suggest that 20i has the potential for development as an AR/AR-V7 inhibitor with degradation ability to treat advanced prostate Cancer.

Figures
Products