ABT-199 inhibits Hedgehog pathway by acting as a competitive inhibitor of oxysterol,rather as a BH3 mimetic

• 作者: Juan Wang Yu Zhang Wen-jing Huang Jun Yang Wei-guo Tang Tao-min Huang Wen-fu Tan
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（6）
• 所属期刊栏目: Chemotherapy
• 页码范围: 1005-1013
• 页数: 9页
• 语种: 英文

摘要

Aberrantly activated Hedgehog(Hh)pathway is critical for driving the initiation and progression of multiple types of cancers,including medulloblastoma(MB)and basal cellular carcinoma(BCC).The majority of current Hh antagonist function by targeting the transmembrane domain of the oncoprotein Smoothened(Smo),a G-protein-coupled receptor-like receptor of Hh pathway.However,the primary and acquired resistance to current Smo inhibitors raise a critical need to develop next-generation of Smo inhibitors to improve their clinical efficacy.In this study,we identify that FDA approved drug ABT-199 significantly and selectively inhibits the Hh pathway.Mechanistically,ABT-199 acts as a competitive inhibitor of oxysterol by potentially targeting the cysteine rich domain(CRD)of Smo,rather as a BH3 mimetic.ABT-199 obviously inhibits the growth of Hh-driven tumors and possesses capacity of combating the primary and acquired resistance to Smo inhibitors caused by Smo mutations.Our data reposition ABT-199 as a Smo inhibitor for treating Hh-driven tumors,especially for those bearing Smo mutations and resistant to current Smo inhibitors.Meanwhile,our findings strengthen the argument that the CRD of Smo is a promising target for developing novel Smo inhibitors with capacity of combating the resistance to Smo inhibitors.