1103500-41-9Relevant academic research and scientific papers
Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer
Han, Xin,Matvekas, Aleksas,McEachern, Donna,Metwally, Hoda,Miao, Bukeyan,Qin, Chong,Sun, Duxin,Wang, Lu,Wang, Shaomeng,Wang, Yu,Wen, Bo,Xiang, Weiguo,Zhao, Lijie
, p. 12831 - 12854 (2021)
Proteolysis targeting chimera (PROTAC) small-molecule degraders have emerged as a promising new type of therapeutic agents, but the design of PROTAC degraders with excellent oral pharmacokinetics is a major challenge. In this study, we present our strategies toward the discovery of highly potent PROTAC degraders of androgen receptor (AR) with excellent oral pharmacokinetics. Employing thalidomide to recruit cereblon/cullin 4A E3 ligase and through the rigidification of the linker, we discovered highly potent AR degraders with good oral pharmacokinetic properties in mice with ARD-2128 being the best compound. ARD-2128 achieves 67% oral bioavailability in mice, effectively reduces AR protein and suppresses AR-regulated genes in tumor tissues with oral administration, leading to the effective inhibition of tumor growth in mice without signs of toxicity. This study supports the development of an orally active PROTAC AR degrader for the treatment of prostate cancer and provides insights and guidance into the design of orally active PROTAC degraders.
ANDROGEN RECEPTOR PROTEIN DEGRADERS WITH A TRICYCLIC CEREBLON LIGAND
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Paragraph 0465-0466, (2021/11/20)
The present disclosure provides compounds represented by Formula I : A-L-B 1 I, and the salts or solvates thereof, wherein A, L, and B1 are as defined in the specification. ompounds having Formula I are androgen receptor degraders useful for the treatment of ancer and other diseases.
