2. Academic Validation
  3. A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened

A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened

  • Cell Chem Biol. 2024 Feb 28:S2451-9456(24)00076-X. doi: 10.1016/j.chembiol.2024.02.002.
Yuan-Bin Liu 1,  Li-Ming He 2,  Ming Sun 1,  Wen-Jun Luo 1,  Zi-Cun Lin 1,  Zhi-Ping Qiu 1,  Yu-Liang Zhang 1,  Ao Hu 1,  Jie Luo 1,  Wen-Wei Qiu 3,  Bao-Liang Song 4
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430000, China.
  • 2 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China.
  • 3 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China. Electronic address: [email protected].
  • 4 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430000, China. Electronic address: [email protected].
PMID: 38442710 DOI: 10.1016/j.chembiol.2024.02.002
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.

Keywords

basal cell carcinomas; cholesterylation; cysteine-rich domain; hedgehog; medulloblastoma; smoothened; vismodegib.

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