| Autor: |
Kudo, Yudai, Endo, Satoshi, Fujita, Mei, Ota, Atsumi, Kamatari, Yuji O., Tanaka, Yoshimasa, Ishikawa, Takeshi, Ikeda, Hayato, Okada, Takuya, Toyooka, Naoki, Fujimoto, Naohiro, Matsunaga, Toshiyuki, Ikari, Akira |
| Zdroj: |
Journal of Medicinal Chemistry; March 2022, Vol. 65 Issue: 6 p4878-4892, 15p |
| Abstrakt: |
Autophagy inhibition is an attractive target for cancer therapy. In this study, we discovered inhibitors of Atg4B essential for autophagosome formation and evaluated their potential as therapeutics for prostate cancer. Seventeen compounds were identified as candidates after in silicoscreening and a thermal shift assay. Among them, compound 17showed the most potent Atg4B inhibitory activity, inhibited autophagy induced by anti-castration-resistant prostate cancer (CRPC) drugs, and significantly enhanced apoptosis. Although 17has been known as a phospholipase A2(PLA2) inhibitor, other PLA2inhibitors had no effect on Atg4B and autophagy. We then performed structural optimization based on molecular modeling and succeeded in developing 21f(by shortening the alkyl chain of 17), which was a potent competitive inhibitor for Atg4B (Ki= 3.1 μM) with declining PLA2inhibitory potency. Compound 21fenhanced the anticancer activity of anti-CRPC drugs viaautophagy inhibition. These findings suggest that 21fcan be used as an adjuvant drug for therapy with anti-CRPC drugs. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
