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Rational Design of RNA Demethylase FTO Inhibitors with Enhanced Antileukemia Drug-Like Properties

文献类型：期刊论文

作者Xiao, Pan4,5; Duan, Zongliang5,6; Liu, Zeyu1,5; Chen, Liang1,5; Zhang, Deyan1,4,5; Liu, Lu4,5; Zhou, Chen2; Gan, Jianhua3; Dong, Ze4,5; Yang, Cai-Guang1,4,5,6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-07-07
页码22
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c00543
通讯作者Dong, Ze(dongze@ucas.ac.cn) ; Yang, Cai-Guang(yangcg@simm.ac.cn)
英文摘要The fat mass and obesity-associated protein (FTO) isan RNA N (6)-methyladenosine (m(6)A) demethylasehighly expressed in diverse cancers including acute myeloid leukemia(AML). To improve antileukemia drug-like properties, we have designed 44/ZLD115, a flexible alkaline side-chain-substituted benzoicacid FTO inhibitor derived from FB23. A combination of structure-activityrelationship analysis and lipophilic efficiency-guided optimizationdemonstrates that 44/ZLD115 exhibits better drug-likenessthan the previously reported FTO inhibitors, FB23 and 13a/Dac85. Then, 44/ZLD115 shows significant antiproliferativeactivity in leukemic NB4 and MOLM13 cell lines. Moreover, 44/ZLD115 treatment noticeably increases m(6)A abundance onthe AML cell RNA, upregulates RARA gene expression,and downregulates MYC gene expression in MOLM13 cells,which are consistent with FTO gene knockdown. Lastly, 44/ZLD115 exhibits antileukemic activity in xenograft micewithout substantial side effects. This FTO inhibitor demonstratespromising properties that can be further developed for antileukemiaapplications.
WOS关键词FAT MASS ; GENE-EXPRESSION ; PROTEIN FTO ; IDENTIFICATION ; METHYLATION ; M(6)A ; DERIVATIVES ; SUBSTRATE
资助项目Instrumentation and Service Center for Molecular Sciences at Westlake University ; National Key Research and Development Program of China[2022YFC2705005] ; National Natural Science Foundation of China[22077133] ; National Natural Science Foundation of China[21725801] ; National Natural Science Foundation of China[92153303] ; Youth Innovation Promotion Association of CAS[2021277]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001022368400001
源URL[http://119.78.100.183/handle/2S10ELR8/306385]  
专题新药研究国家重点实验室
通讯作者Dong, Ze; Yang, Cai-Guang
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Analyt Res Ctr Organ & Biol Mol, Shanghai 201203, Peoples R China
3.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Nanjing Univ Chinese Med, Coll Pharm, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Xiao, Pan,Duan, Zongliang,Liu, Zeyu,et al. Rational Design of RNA Demethylase FTO Inhibitors with Enhanced Antileukemia Drug-Like Properties[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023:22.
APA Xiao, Pan.,Duan, Zongliang.,Liu, Zeyu.,Chen, Liang.,Zhang, Deyan.,...&Yang, Cai-Guang.(2023).Rational Design of RNA Demethylase FTO Inhibitors with Enhanced Antileukemia Drug-Like Properties.JOURNAL OF MEDICINAL CHEMISTRY,22.
MLA Xiao, Pan,et al."Rational Design of RNA Demethylase FTO Inhibitors with Enhanced Antileukemia Drug-Like Properties".JOURNAL OF MEDICINAL CHEMISTRY (2023):22.

入库方式： OAI收割

来源：上海药物研究所

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