Development of hedgehog pathway inhibitors by epigenetically targeting GLI through BET bromodomain for the treatment of medulloblastoma

doi:10.1016/j.apsb.2020.07.007

	Development of hedgehog pathway inhibitors by epigenetically targeting GLI through BET bromodomain for the treatment of medulloblastoma
	Liu, Xiaohua 1,4,6; Zhang, Yu 2; Li, Yalei 3; Wang, Juan 2; Ding, Huaqian 1,6; Huang, Wenjing 2; Ding, Chunyong 1,4; Liu, Hongchun 3; Tan, Wenfu 2; Zhang, Ao1,4,5,6,7
	2021-02
发表期刊	ACTA PHARMACEUTICA SINICA B (IF:14.7[JCR-2023],14.1[5-Year])
ISSN	2211-3835
EISSN	2211-3843
卷号	11 期号:2 页码:488-504
DOI	10.1016/j.apsb.2020.07.007
摘要	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 2 was selected as the lead for further structural optimization, which led to the identification of compounds 25 and 35 as the high potency HH inhibitors. Mechanism profiling showed that both compounds suppressed HH signaling by interacting with the transcriptional factor GLI, and were equally potent against the clinical resistant mutants and the wild type of smoothened (SMO) receptor with IC50 values around 1 nmol/L. In the resistant MB allograft mice, compound 25 was well tolerated and markedly suppressed tumor growth at both 5 mg/kg (TGI = 83.3%) and 10 mg/kg (TGI = 87.6%) doses. Although further modification is needed to improve the pharmacokinetic (PK) parameters, compound 25 represents an efficacious lead compound of GLI inhibitors, possessing optimal safety and tolerance to fight against HH-driven MB. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
关键词	Medulloblastoma Hedgehog signaling pathway Drug resistance GLI BRD4
收录类别	SCI ; SCIE
语种	英语
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Pharmacology & Pharmacy
WOS记录号	WOS:000617944700013
出版者	INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS关键词	DISCOVERY ; RESISTANCE ; GROWTH ; POTENT ; TRANSCRIPTION ; STRATEGIES ; VISMODEGIB ; RECURRENT
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/125831
专题	生命科学与技术学院_特聘教授组_张翱组
通讯作者	Liu, Hongchun; Tan, Wenfu; Zhang, Ao
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Shanghai Jiao Tong Univ, Sch Pharm, Shanghai 200240, Peoples R China; 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China; 6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 7.Zhengzhou Univ, State Key Lab Esophageal Canc Prevent & Treatment, Minist Educ China, Zhengzhou 450001, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Liu, Xiaohua,Zhang, Yu,Li, Yalei,et al. Development of hedgehog pathway inhibitors by epigenetically targeting GLI through BET bromodomain for the treatment of medulloblastoma[J]. ACTA PHARMACEUTICA SINICA B,2021,11(2):488-504.
APA	Liu, Xiaohua.,Zhang, Yu.,Li, Yalei.,Wang, Juan.,Ding, Huaqian.,...&Zhang, Ao.(2021).Development of hedgehog pathway inhibitors by epigenetically targeting GLI through BET bromodomain for the treatment of medulloblastoma.ACTA PHARMACEUTICA SINICA B,11(2),488-504.
MLA	Liu, Xiaohua,et al."Development of hedgehog pathway inhibitors by epigenetically targeting GLI through BET bromodomain for the treatment of medulloblastoma".ACTA PHARMACEUTICA SINICA B 11.2(2021):488-504.