Antarlides: A New Type of Androgen Receptor (AR) Antagonist that Overcomes Resistance to AR‐Targeted Therapy. Issue 8 (25th January 2016)

• Record Type: Journal Article
• Authors: Saito, Shun; Fujimaki, Takahiro; Panbangred, Watanalai; Igarashi, Yasuhiro; Imoto, Masaya
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 8(2016)
• Page Start: 2728
• Page End: 2732
• Publication Date: 2016-01-25
• Subjects: androgen receptor antagonists -- cancer -- drug resistance -- natural products -- NMR spectroscopy; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201510079
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Prostate cancer is treated with androgen receptor (AR) antagonists but most patients experience disease progression after long‐term treatment with these compounds. Therefore, new AR antagonists are required for patient follow‐up treatment. In the course of screening for a new AR antagonist, we isolated the novel compounds antarlides A–E (1 –5 ) from Streptomyces sp. BB47. Antarlides are mutually isomeric with respect to the double bond and have a 22‐membered‐ring macrocyclic structure. The full stereostructure of 1 was established by chemical modifications, including methanolysis, the Trost method, acetonide formation, and the PGME method. 1 –5 inhibited the binding of androgen to ARs in vitro. In addition, 2 inhibited the transcriptional activity of not only wild‐type AR but also mutant ARs, which are seen in patients with acquired resistance to clinically used AR antagonists. Therefore, antarlides are a potent new generation of AR antagonists that overcome resistance. Abstract : The next generation : Advanced prostate cancer is treated with androgen receptor (AR) antagonists, but most patients experience disease progression after long‐term treatment with these antagonists. Antarlides, isolated from Streptomyces sp. BB47, inhibited the transcriptional activity of mutant ARs, which are seen in patients with acquired resistance to the current clinically used drug enzalutamide (XTANDI).