A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened

Yuan-Bin Liu; Li-Ming He; Ming Sun; Wen-Jun Luo; Zi-Cun Lin; Zhi-Ping Qiu; Yu-Liang Zhang; Ao Hu; Jie Luo; Wen-Wei Qiu; Bao-Liang Song

doi:10.1016/j.chembiol.2024.02.002

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. Online ahead of print.

Authors

Yuan-Bin Liu¹, Li-Ming He², Ming Sun¹, Wen-Jun Luo¹, Zi-Cun Lin¹, Zhi-Ping Qiu¹, Yu-Liang Zhang¹, Ao Hu¹, Jie Luo¹, Wen-Wei Qiu³, Bao-Liang Song⁴

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: wwqiu@chem.ecnu.edu.cn.
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: blsong@whu.edu.cn.

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.