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

Jinbiao Liao; Jianing Liao; Minkui Zhang; Yanzhen Yu; Lvtao Cai; Kaixin Le; Weitao Fu; Yiyang Qin; Tingjun Hou; Dan Li; Rong Sheng

doi:10.1021/acs.jmedchem.4c01752

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

J Med Chem. 2024 Nov 4. doi: 10.1021/acs.jmedchem.4c01752. Online ahead of print.

Authors

Jinbiao Liao¹, Jianing Liao¹, Minkui Zhang¹, Yanzhen Yu¹, Lvtao Cai^{1

2}, Kaixin Le^{1

2}, Weitao Fu¹, Yiyang Qin¹, Tingjun Hou¹, 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 AR^F876L/T877A and AR^W741C 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.