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 1,3,6; Zhang, Yu 4; Li, Yalei 5; Wang, Juan 4; Ding, Huaqian 1,3; Huang, Wenjing 4; Ding, Chunyong 3,6; Liu, Hongchun 5; Tan, Wenfu 4; Zhang, Ao 1,2,3,6,7
刊名	ACTA PHARMACEUTICA SINICA B
	2021-02-01
卷号	11 期号:2 页码:488-504
关键词	Medulloblastoma Hedgehog signaling pathway Drug resistance GLI BRD4
ISSN号	2211-3835
DOI	10.1016/j.apsb.2020.07.007
通讯作者	Liu, Hongchun(hchliu@simm.ac.cn) ; Tan, Wenfu(wftan@fudan.edu.cn) ; Zhang, Ao(ao6919zhang@sjtu.edu.cn)
英文摘要	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.
资助项目	National Natural Science Foundation[81773565] ; National Natural Science Foundation[81703327] ; National Natural Science Foundation[81430080] ; National Natural Science Foundation[81573452] ; National Natural Science Foundation[81773767] ; Key Program of the Frontier Science, China of the Chinese Academy of Sciences[160621] ; Strategic Priority Research Program of the Chinese Academy of Sciences, China[XDA12020374] ; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Ministry of Education of China, Zhengzhou University, China[K2020-0012]
WOS关键词	DISCOVERY ; RESISTANCE ; GROWTH ; POTENT ; TRANSCRIPTION ; STRATEGIES ; VISMODEGIB ; RECURRENT
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号	WOS:000617944700013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295682]
专题	中国科学院上海药物研究所
通讯作者	Liu, Hongchun; Tan, Wenfu; Zhang, Ao
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Zhengzhou Univ, State Key Lab Esophageal Canc Prevent & Treatment, Minist Educ China, Zhengzhou 450001, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 4.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, State Key Lab Drug Res, Shanghai 201203, Peoples R China 6.Shanghai Jiao Tong Univ, Sch Pharm, Shanghai 200240, Peoples R China 7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
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.