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Discovery of MTR-106 as a highly potent G-quadruplex stabilizer for treating BRCA-deficient cancers

文献类型：期刊论文

作者Li, Meng-Zhu1,2; Meng, Tao2,3; Song, Shan-Shan1,2; Bao, Xu-Bin1,2; Ma, Lan-Ping2,3; Zhang, Ning1,2; Yu, Ting2,3; Zhang, Yong-Liang2,3; Xiong, Bing2,3; Shen, Jing-Kang2,3
刊名INVESTIGATIONAL NEW DRUGS
出版日期2021-03-12
页码9
关键词G-quadruplex stabilizer MTR-106 BRCA-deficiency PARP inhibitor DNA damage
ISSN号0167-6997
DOI10.1007/s10637-021-01096-4
通讯作者Xiong, Bing(bxiong@simm.ac.cn) ; Shen, Jing-Kang(jkshen@simm.ac.cn) ; Miao, Ze-Hong(zhmiao@simm.ac.cn) ; He, Jin-Xue(jinxue_he@simm.ac.cn)
英文摘要G-quadruplexes (G4s) are DNA or RNA structures formed by guanine-rich repeating sequences. Recently, G4s have become a highly attractive therapeutic target for BRCA-deficient cancers. Here, we show that a substituted quinolone amide compound, MTR-106, stabilizes DNA G-quadruplexes in vitro. MTR-106 displayed significant antiproliferative activity in homologous recombination repair (HR)-deficient and PARP inhibitor (PARPi)-resistant cancer cells. Moreover, MTR-106 increased DNA damage and promoted cell cycle arrest and apoptosis to inhibit cell growth. Importantly, its oral and i.v. administration significantly impaired tumor growth in BRCA-deficient xenograft mouse models. However, MTR-106 showed modest activity against talazoparib-resistant xenograft models. In rats, the drug rapidly distributes to tissues within 5 min, and its average concentrations were 12-fold higher in the tissues than in the plasma. Overall, we identified MTR-106 as a novel G-quadruplex stabilizer with high tissue distribution, and it may serve as a potential anticancer agent.
资助项目National Natural Science Foundation of China[82,073,875] ; National Natural Science Foundation of China[82,073,865] ; National Natural Science Foundation of China[81,773,764] ; Chinese Academy of Sciences[29,201,731,121,100,101] ; Chinese Academy of Sciences[XDA12020104] ; Chinese Academy of Sciences[XDA12020109] ; Chinese Academy of Sciences[CASIMM0120185003] ; Science and Technology Commission of Shanghai Municipality[19QA1410900] ; State Key Laboratory of Drug Research ; SA-SIBS Scholarship Program
WOS研究方向Oncology ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000628121100001
出版者SPRINGER
源URL[http://119.78.100.183/handle/2S10ELR8/295536]  
专题新药研究国家重点实验室
通讯作者Xiong, Bing; Shen, Jing-Kang; Miao, Ze-Hong; He, Jin-Xue
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Li, Meng-Zhu,Meng, Tao,Song, Shan-Shan,et al. Discovery of MTR-106 as a highly potent G-quadruplex stabilizer for treating BRCA-deficient cancers[J]. INVESTIGATIONAL NEW DRUGS,2021:9.
APA Li, Meng-Zhu.,Meng, Tao.,Song, Shan-Shan.,Bao, Xu-Bin.,Ma, Lan-Ping.,...&He, Jin-Xue.(2021).Discovery of MTR-106 as a highly potent G-quadruplex stabilizer for treating BRCA-deficient cancers.INVESTIGATIONAL NEW DRUGS,9.
MLA Li, Meng-Zhu,et al."Discovery of MTR-106 as a highly potent G-quadruplex stabilizer for treating BRCA-deficient cancers".INVESTIGATIONAL NEW DRUGS (2021):9.

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来源：上海药物研究所

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