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Discovery of Thiochroman Derivatives as Potent, Oral Selective Estrogen Receptor Degraders and Antagonists for the Treatment of Endocrine-Resistant Breast Cancer

文献类型：期刊论文

作者Zhang, Dan3; Lu, Zhengyu3; He, Yongqi1,3; Leng, Xin-Yu3,4; Meng, Xin4; Lei, Xiang1,3; Kong, Deyu3; Sun, Lulu3; Hu, Wenhao2; Yang, Yushe3,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-11-29
卷号67期号:23页码:21545-21567
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c02453
英文摘要Selective estrogen receptor degraders (SERDs) deplete the ER signaling pathway via antagonism and degradation of ER alpha and represent a promising strategy to tackle endocrine resistance. Here, we report a new class of SERDs by pharmacological evolution of a selective estrogen receptor modulator, lasofoxifene. The structure-activity relationship study and efforts to circumvent the issue of human ether-a-go-go-related gene led to the identification of compounds 51. This bifunctional compound displayed broad activity across a vast array of cell backgrounds and was capable of effectively degrading and antagonizing wild-type ER alpha and clinically relevant ER alpha mutants. 51 exhibited favorable pharmacokinetic properties and good brain penetration, with a brain/plasma ratio of 3.05, and significantly suppressed the growth of tumor in a tamoxifen-resistant MCF-7 Tam1 xenograft model. Overall, the study demonstrates 51 as a highly potent, oral, and brain penetrant ER degrader and pure antagonist, showing a good potential in overcoming endocrine resistance.
WOS关键词ANTITUMOR-ACTIVITY ; ER ; FULVESTRANT ; MECHANISMS ; AZD9496 ; THERAPY ; RAD1901 ; SERDS
资助项目Youth Innovation Promotion Association of the Chinese Academy of Sciences[2021275] ; Youth Innovation Promotion Association of Chinese Academy of Sciences
WOS研究方向Pharmacology & Pharmacy
WOS记录号WOS:001367646300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/314771]  
专题新药研究国家重点实验室
通讯作者Hu, Wenhao; Yang, Yushe
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangdong Key Lab Chiral Mol & Drug Discovery, Guangzhou 510006, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Dan,Lu, Zhengyu,He, Yongqi,et al. Discovery of Thiochroman Derivatives as Potent, Oral Selective Estrogen Receptor Degraders and Antagonists for the Treatment of Endocrine-Resistant Breast Cancer[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(23):21545-21567.
APA Zhang, Dan.,Lu, Zhengyu.,He, Yongqi.,Leng, Xin-Yu.,Meng, Xin.,...&Yang, Yushe.(2024).Discovery of Thiochroman Derivatives as Potent, Oral Selective Estrogen Receptor Degraders and Antagonists for the Treatment of Endocrine-Resistant Breast Cancer.JOURNAL OF MEDICINAL CHEMISTRY,67(23),21545-21567.
MLA Zhang, Dan,et al."Discovery of Thiochroman Derivatives as Potent, Oral Selective Estrogen Receptor Degraders and Antagonists for the Treatment of Endocrine-Resistant Breast Cancer".JOURNAL OF MEDICINAL CHEMISTRY 67.23(2024):21545-21567.

入库方式： OAI收割

来源：上海药物研究所

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