平滑
维莫德吉
刺猬信号通路
刺猬
基底细胞癌
癌症研究
抑制性突触后电位
生物
细胞生物学
化学
信号转导
药理学
内科学
医学
内分泌学
基底细胞
作者
Yuanbin Liu,Lin He,Ming Sun,Wei Luo,Zi-Cun Lin,Zhiping Qiu,Yuliang Zhang,Ao Hu,Jie Luo,Wen‐Wei Qiu,Bao-Liang Song
标识
DOI:10.1016/j.chembiol.2024.02.002
摘要
The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.
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