Identification of Oral Bioavailable Coumarin Derivatives as Potential AR Antagonists Targeting Prostate Cancer

  • J Med Chem. 2024 Nov 14;67(21):19395-19416. doi: 10.1021/acs.jmedchem.4c01752.
Jinbiao Liao  1 ,  Jianing Liao  1 ,  Minkui Zhang  1 ,  Yanzhen Yu  1 ,  Lvtao Cai  1  2 ,  Kaixin Le  1  2 ,  Weitao Fu  1 ,  Yiyang Qin  1 ,  Tingjun Hou  1 ,  Dan Li  1  2 ,  Rong Sheng  1  2
Affiliations
  • 1. State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 2. Jinhua Institute of Zhejiang University, Jinhua 321000 Zhejiang, China.
PMID: 39492719 DOI: 10.1021/acs.jmedchem.4c01752
Abstract

Androgen Receptor (AR) is a crucial driver of prostate Cancer (PCa), but acquired resistance to AR antagonists significantly undermines their clinical efficacy. We previously discovered coumarin derivative 1, which is capable of disrupting AR ligand-binding domain dimers, offering the potential for overcoming resistance. However, its poor oral bioavailability limited further development. In this study, comprehensive structure optimizations led to compound 4a (IC50 = 0.051 μM), which exhibited comparable AR antagonistic activity to enzalutamide (IC50 = 0.060 μM) and demonstrated excellent selectivity over Other nuclear receptors in vitro. Especially, 4a showed superior efficacy against ARF876L/T877A and ARW741C mutants compared to darolutamide and enzalutamide. Moreover, 4a exhibited favorable pharmacokinetic profiles (F = 66.24%) in vivo and significant tumor growth inhibition in an LNCaP xenograft mouse model upon oral administration. These results highlight the potential of 4a as a promising oral AR antagonist for overcoming drug resistance in PCa.

Products