Structure-Activity Relationship of SPOP Inhibitors against Kidney Cancer

doi:10.1021/acs.jmedchem.0c00161

	Structure-Activity Relationship of SPOP Inhibitors against Kidney Cancer
	Dong, Ze 3; Wang, Zhen 3,5; Guo, Zhong-Qiang 1,6; Gong, Shouzhe 3; Zhang, Tao 3; Liu, Jiang 1; Luo, Cheng 3,4; Jiang, Hualiang 2,3,4; Yang, Cai-Guang 3,4
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2020-05-14
卷号	63 期号:9 页码:4849-4866
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.0c00161
通讯作者	Yang, Cai-Guang(yangcg@simm.ac.cn)
英文摘要	Speckle-type POZ protein (SPOP) is overexpressed in the nucleus and misallocated in the cytoplasm in almost all the clear-cell renal cell carcinomas (ccRCCs), which leads to kidney tumorigenesis. Previously, we elucidated that the oncogenic SPOP-signaling pathway in ccRCC could be suppressed by 6b that inhibits SPOP-mediated protein interactions. Herein, we have established a structure-activity relationship for 6b analogues as SPOP inhibitors. Compound 6lc suppresses the viability and inhibits the colony formation of ccRCC cell lines driven by cytoplasmic SPOP, superior to 6b. Compound 6lc binds to the SPOP protein in vitro and disrupts SPOP binding to phosphatase-and-tensin homologue (PTEN) in HEK293T cells, which causes the observable phenomena: a decline in the ubiquitination of PTEN, elevated levels of both PTEN and dual-specificity phosphatase 7, and decreased levels of phosphorylated AKT and ERK when ccRCC cell lines are exposed to 6lc in a dose-response manner. Taken together, compound 6lc is a potent candidate against kidney tumorigenesis.
资助项目	National Natural Science Foundation of China[21807103] ; National Natural Science Foundation of China[21725801] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002]
WOS关键词	POZ PROTEIN SPOP ; ADAPTER ; DESIGN
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000535279800029
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280052]
专题	中国科学院上海药物研究所
通讯作者	Yang, Cai-Guang
作者单位	1.Chinese Acad Sci, CAS Key Lab Genome Sci & Informat, Beijing Inst Genom, Beijing 100101, Peoples R China 2.ShanghaiTec Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 3.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 4.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, UCAS, Hangzhou 310024, Peoples R China 5.Nanjing Univ Chinese Med, Coll Pharm, Nanjing 210023, Peoples R China 6.Wuhan Univ, Dept Urol, Zhongnan Hosp, Wuhan 430071, Hubei, Peoples R China
推荐引用方式 GB/T 7714	Dong, Ze,Wang, Zhen,Guo, Zhong-Qiang,et al. Structure-Activity Relationship of SPOP Inhibitors against Kidney Cancer[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(9):4849-4866.
APA	Dong, Ze.,Wang, Zhen.,Guo, Zhong-Qiang.,Gong, Shouzhe.,Zhang, Tao.,...&Yang, Cai-Guang.(2020).Structure-Activity Relationship of SPOP Inhibitors against Kidney Cancer.JOURNAL OF MEDICINAL CHEMISTRY,63(9),4849-4866.
MLA	Dong, Ze,et al."Structure-Activity Relationship of SPOP Inhibitors against Kidney Cancer".JOURNAL OF MEDICINAL CHEMISTRY 63.9(2020):4849-4866.