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引用次数: 0
摘要
由于在细胞增殖和肿瘤发生中的重要作用,刺猬(Hh)信号通路一直是抗癌药物研发的热点。然而,临床上现有的Hh通路抑制剂大多以平滑肌(SMO)的七跨膜区(7TM)为靶点,获得性耐药性是SMO抑制疗法亟待解决的问题。在这里,我们发现了一种甾醇类似物 Q29,并证明它能通过与 SMO 的富半胱氨酸结构域(CRD)结合并阻断其胆固醇化来抑制 Hh 通路。Q29 可抑制 Hh 信号依赖性细胞增殖,并抑制 Hh 依赖性髓母细胞瘤的生长。Q29 与临床上用于治疗基底细胞癌(BCC)的 SMO-7TM 抑制剂 vismodegib 对髓母细胞瘤具有相加抑制作用。重要的是,Q29 能克服 SMO 突变体对 SMO-7TM 抑制剂产生的抗药性,并抑制 SMO 致癌变体的活性。我们的工作表明,SMO-CRD抑制剂可以成为治疗Hh通路驱动的癌症的一种新方法。
A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened
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.
Cell Chemical BiologyBiochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
14.70
自引率
2.30%
发文量
143
期刊介绍:
Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.