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Discovery of Thieno[2,3-e]indazole Derivatives as Novel Oral Selective Estrogen Receptor Degraders with Highly Improved Antitumor Effect and Favorable Druggability br

文献类型：期刊论文

作者Lu, Zhengyu2,3; Cao, Yangzhi2,3; Zhang, Dan3; Meng, Xin3; Guo, Bin2,3; Kong, Deyu1; Yang, Yushe2,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-04-14
卷号65期号:7页码:5724-5750
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c00008
通讯作者Guo, Bin(guobin@simm.ac.cn) ; Kong, Deyu(ydekong@163.com) ; Yang, Yushe(ysyang@simm.ac.cn)
英文摘要Endocrine therapies in the treatment of early and metastatic estrogen receptor alpha positive (ER alpha+) breast cancer (BC)are greatly limited byde novoand acquired resistance. Selective estrogen receptor degraders (SERDs) like fulvestrant provide newstrategies for endocrine therapy combinations due to unique mechanisms. Herein, we disclose our structure-based optimization ofLSZ102 by replacing 6-hydroxybenzothiophene with 6H-thieno[2,3-e]indazole. Subsequent acrylic acid degron modifications led usto identify compound40as the preferred candidate. In general, compound40showed much better pharmacological profiles than the lead LSZ102, exhibiting growth inhibition of wild-type or tamoxifen-resistant MCF-7 cells, potent ER alpha degradation, together with superior pharmacokinetic properties, directional target tissue distribution including the brain, and robust antitumor efficacy in the mice breast cancer xenograft model. Currently,40is being evaluated in preclinical trials
WOS关键词BREAST-CANCER ; NONSTEROIDAL ESTROGEN ; ENDOCRINE RESISTANCE ; DRUG DISCOVERY ; ER ; TAMOXIFEN ; POTENT ; ACID ; IDENTIFICATION ; ALPHA
资助项目National Natural Science Foundation of China[81973165] ; Youth Innovation Promotion Association of Chinese Academy of Sciences
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000792282200031
源URL[http://119.78.100.183/handle/2S10ELR8/300986]  
专题新药研究国家重点实验室
通讯作者Guo, Bin; Kong, Deyu; Yang, Yushe
作者单位1.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Sch Chem & Mol Engn, Shanghai 200062, Peoples R China
2.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Lu, Zhengyu,Cao, Yangzhi,Zhang, Dan,et al. Discovery of Thieno[2,3-e]indazole Derivatives as Novel Oral Selective Estrogen Receptor Degraders with Highly Improved Antitumor Effect and Favorable Druggability br[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(7):5724-5750.
APA Lu, Zhengyu.,Cao, Yangzhi.,Zhang, Dan.,Meng, Xin.,Guo, Bin.,...&Yang, Yushe.(2022).Discovery of Thieno[2,3-e]indazole Derivatives as Novel Oral Selective Estrogen Receptor Degraders with Highly Improved Antitumor Effect and Favorable Druggability br.JOURNAL OF MEDICINAL CHEMISTRY,65(7),5724-5750.
MLA Lu, Zhengyu,et al."Discovery of Thieno[2,3-e]indazole Derivatives as Novel Oral Selective Estrogen Receptor Degraders with Highly Improved Antitumor Effect and Favorable Druggability br".JOURNAL OF MEDICINAL CHEMISTRY 65.7(2022):5724-5750.

入库方式： OAI收割

来源：上海药物研究所

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