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 

机构地区：[1]Department of Pharmacology,School of Pharmacy,Fudan University,Shanghai 201203,China [2]Minhang Hospital,Fudan University,Shanghai 201203,China [3]Institute of Fudan-Minhang Academic Health System,Minhang Hospital,Fudan University,Shanghai 201203,China [4]Department of Pharmacy,Eye&ENT Hospital,Shanghai Medical College,Fudan University,Shanghai 200031,China

出　　处：《Acta Pharmacologica Sinica》2021年第6期1005-1013,共9页中国药理学报（英文版）

基　　金：This work was financially supported by grants from National Natural Science Foundation of China(No.81773767,81573452);We also appreciate Fudan-SIMM Joint Research Fund(No.FU-SIMM20181005);MHHFDU-SPFDU Joint Research Fund(No.RO-MY201805);the fund from State Key Laboratory of Drug Research(No SIMM1903KF-12).

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.

关 键 词：Hedgehog SMOOTHENED cysteine rich domain MEDULLOBLASTOMA basal cellular carcinoma 

分 类 号：R965[医药卫生—药理学]