Journal
BIOORGANIC CHEMISTRY
Volume 124, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.105829
Keywords
CRPC; Androgen receptor antagonist; Darolutamide; Structure-activity relationship
Funding
- Nature Science Foundation of China [22077115, 81672559, 81311120299]
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The androgen signaling pathway is crucial in prostate cancer (PCa), and the anti-androgen drug Darolutamide (ODM-201) shows promising activity against the androgen receptor. This study synthesized 37 analogues of ODM-201 with half of them exhibiting similar or better anti-AR transcriptional activity, and compound 28t showed superior inhibitory activity against resistant mutants.
Androgen signaling pathway plays an important role in the occurrence and development of prostate cancer (PCa), and anti-androgen drugs are one of the most effective therapies for PCa. Darolutamide 4 (ODM-201) is a promising second-generation antiandrogen because of its unique chemical structure and good activity against androgen receptor (AR). Herein, the structure-activity relationship of ODM-201 was studied, and 37 analogues were synthesized. Half of them exhibited similar or better anti-AR transcriptional activity compared to ODM-201. In addition, the inhibitory activity of compound 28t against the two resistant mutants (AR-F876L and AR-T877A) was superior to that of ODM-201. This study provides a new clue for the further optimization of ODM-201 and the development of anti-CRPC drugs.
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