期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 18, 页码 13487-13509出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00900
关键词
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资金
- Roivant Sciences
- National Cancer Institute, NIH [P50 CA186786]
- University of Michigan Comprehensive Cancer Center Core Grant from the National Cancer Institute, NIH [P30CA046592]
This study identifies a promising AR degrader for the treatment of advanced prostate cancer, which demonstrates potent inhibition in cell lines with AR gene amplification or mutations and shows good oral bioavailability in mice.
We report herein the discovery of exceptionally potent and orally bioavailable PROTAC AR degraders with ARD-2585 being the most promising compound. ARD-2585 achieves DC50 values of <= 0.1 nM in the VCaP cell line with AR gene amplification and in the LNCaP cell line carrying an AR mutation. It potently inhibits cell growth with IC50 values of 1.5 and 16.2 nM in the VCaP and LNCaP cell lines, respectively, and achieves excellent pharmacokinetics and 51% of oral bioavailability in mice. It is more efficacious than enzalutamide in inhibition of VCaP tumor growth and does not cause any sign of toxicity in mice. ARD-2585 is a promising AR degrader for extensive investigations for the treatment of advanced prostate cancer.
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