Development of hedgehog pathway inhibitors by epigenetically targeting GLI through BET bromodomain for the treatment of medulloblastoma.
10.1016/j.apsb.2020.07.007
- Author:
Xiaohua LIU
1
;
Yu ZHANG
2
;
Yalei LI
3
;
Juan WANG
2
;
Huaqian DING
1
;
Wenjing HUANG
2
;
Chunyong DING
1
;
Hongchun LIU
3
;
Wenfu TAN
2
;
Ao ZHANG
1
Author Information
1. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
2. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
- Publication Type:Journal Article
- Keywords:
BCC, basal cell carcinoma;
BET, bromo and extra C-terminal bromodomain proteins;
BRD4;
BRD4, bromodomain-containing protein 4;
Drug resistance;
GLI;
HH, hedgehog;
HTRF, homogeneous time-resolved fluorescence;
Hedgehog signaling pathway;
MB, medulloblastoma;
Medulloblastoma;
PK, pharmacokinetic;
PTCH, patched;
SAR, structure−activity relationship;
SHH, Sonic hedgehog;
SMO, smoothened;
TGI, tumor growth inhibition;
WNT, wingless;
hERG, human ether-a-go-go-related gene;
i.v., intravenous injection;
p.o., per os
- From:
Acta Pharmaceutica Sinica B
2021;11(2):488-504
- CountryChina
- Language:English
-
Abstract:
Medulloblastoma (MB) is a common yet highly heterogeneous childhood malignant brain tumor, however, clinically effective molecular targeted therapy is lacking. Modulation of hedgehog (HH) signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4 (BRD4) has recently spurred new interest as potential treatment of HH-driven MB. Through screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated oncogene homolog (GLI) protein, the BRD4 inhibitor
