Discovery of ARD-2585 as an Exceptionally Potent and Orally Active PROTAC Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer
| Autor: | Bo Wen, Shaomeng Wang, Duxin Sun, Miao He, Paul D. Kirchhoff, Weiguo Xiang, Chong Qin, Xin Han, Donna McEachern, Lu Wang, Hoda Metwally, Aleksas Matvekas, Lijie Zhao, Yu Wang, Bukeyan Miao |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Antineoplastic Agents Phthalimides Mice SCID Article Structure-Activity Relationship chemistry.chemical_compound Prostate cancer Pharmacokinetics Cell Line Tumor Drug Discovery LNCaP Androgen Receptor Antagonists medicine Animals Humans Enzalutamide Piperidones Adaptor Proteins Signal Transducing Molecular Structure Cell growth medicine.disease Xenograft Model Antitumor Assays Androgen receptor Prostatic Neoplasms Castration-Resistant chemistry Receptors Androgen Cell culture Drug Design Proteolysis Toxicity Cancer research Molecular Medicine |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00900 |
| Popis: | 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 DC(50) 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 IC(50) 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. |
| Databáze: | OpenAIRE |
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