1. A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened.
- Author
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Liu YB, He LM, Sun M, Luo WJ, Lin ZC, Qiu ZP, Zhang YL, Hu A, Luo J, Qiu WW, and Song BL
- Subjects
- Humans, Animals, Mice, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Molecular Structure, Cholesterol metabolism, Smoothened Receptor antagonists & inhibitors, Smoothened Receptor metabolism, Hedgehog Proteins metabolism, Hedgehog Proteins antagonists & inhibitors, Signal Transduction drug effects, Cell Proliferation drug effects, Sterols chemistry, Sterols pharmacology, Sterols metabolism, Medulloblastoma drug therapy, Medulloblastoma metabolism, Medulloblastoma pathology
- Abstract
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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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