Synthesis and biological evaluation of novel benzamide derivatives as potent smoothened antagonists.
A series of novel benzamide derivatives were prepared and evaluated using cell-based measurements. Among these compounds, 10f significantly inhibited Hedgehog signaling and showed equivalent or more potency than GDC-0449 in different tests. Furthermore, compound 10f potently inhibited the proliferation of Daoy, a medulloblastoma cell line that is reported to be resistant to GDC-0449, which indicated a promising prospect in the treatment of Hedgehog signaling pathway related cancer in clinical trial.
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Tian-Ming
TM
Wu
Department of Pharmaceutical and Biological Engineering, College of Chemical Engineering, Sichuan University, Chengdu 610065, China.
Dao-Cai
DC
Wang
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Pu
P
Xiang
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Jian-Nan
JN
Zhang
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Ya-Xiong
YX
Sang
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Hong-Jun
HJ
Lin
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Jie
J
Chen
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Gang
G
Xie
Department of Pharmaceutical and Biological Engineering, College of Chemical Engineering, Sichuan University, Chengdu 610065, China.
Hang
H
Song
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. Electronic address: zhaoyinglan@scu.edu.cn.
Ying-Lan
YL
Zhao
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. Electronic address: xieym@scu.edu.cn.
Yong-Mei
YM
Xie
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015027:Zebrafish
D001549:Benzamides; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D013450:Sulfones; C037689:benzamide
Amide derivatives; Hedgehog; Smoothened antagonist