YCH1899, a Highly Effective Phthalazin-1(2H)-one Derivative That Overcomes Resistance to Prior PARP Inhibitors
文献类型：期刊论文
| 作者 | Sun, Yuting1,2; Yang, Hui2,3; Yuan, Jiaqi1,2; Wang, Limin2,3; Song, Shanshan2,3; Chen, Rongrong1,4; Bao, Xubin2,3; Jia, Li2,3; Yang, Tiantian1,2; Zhang, Xiaofei1 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2023-08-22 |
| 页码 | 20 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.3c00821 |
| 通讯作者 | Miao, Zehong(zhmiao@simm.ac.cn) ; He, Jinxue(jinxue_he@simm.ac.cn) ; Yang, Chunhao(chyang@simm.ac.cn) |
| 英文摘要 | Poly(ADP-ribose)polymerase inhibitors (PARPi) have significantefficacy in treating BRCA-deficient cancers, although resistance developmentremains an unsolved challenge. Herein, a series of phthalazin-1(2H)-one derivatives with excellent enzymatic inhibitory activitywere designed and synthesized, and the structure-activity relationshipwas explored. Compared with olaparib and talazoparib, compound YCH1899 exhibited distinct antiproliferation activity againstolaparib- and talazoparib-resistant cells, with IC50 valuesof 0.89 and 1.13 nM, respectively. Studies of the cellular mechanismrevealed that YCH1899 retained sensitivity in drug-resistantcells with BRCA1/2 restoration or 53BP1 loss. Furthermore, YCH1899 had acceptable pharmacokinetic properties in rats and showed prominentdose-dependent antitumor activity in olaparib- and talazoparib-resistantcell-derived xenograft models. Overall, this study suggests that YCH1899 is a new-generation antiresistant PARPi that couldprovide a valuable direction for addressing drug resistance to existingPARPi drugs. |
| WOS关键词 | POLY(ADP-RIBOSE) POLYMERASE ; DNA-DAMAGE ; ACQUIRED-RESISTANCE ; THERAPY ; REPAIR ; CELLS ; OLAPARIB ; 53BP1 |
| 资助项目 | National Natural Science Foundation of China[82073875] ; National Natural Science Foundation of China[82073865] ; Chinese Academy of Sciences[29201731121100101] ; Chinese Academy of Sciences[XDA12010306] ; Chinese Academy of Sciences[CASIMM0120185003] ; Science and Technology Commission of Shanghai Municipality (Shanghai Rising-Star Program)[19QA1410900] ; State Key Laboratory of Drug Research ; SA-SIBS Scholarship Program |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001052054600001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/306989]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Miao, Zehong; He, Jinxue; Yang, Chunhao |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China |
| 推荐引用方式 GB/T 7714 | Sun, Yuting,Yang, Hui,Yuan, Jiaqi,et al. YCH1899, a Highly Effective Phthalazin-1(2H)-one Derivative That Overcomes Resistance to Prior PARP Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023:20. |
| APA | Sun, Yuting.,Yang, Hui.,Yuan, Jiaqi.,Wang, Limin.,Song, Shanshan.,...&Yang, Chunhao.(2023).YCH1899, a Highly Effective Phthalazin-1(2H)-one Derivative That Overcomes Resistance to Prior PARP Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,20. |
| MLA | Sun, Yuting,et al."YCH1899, a Highly Effective Phthalazin-1(2H)-one Derivative That Overcomes Resistance to Prior PARP Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY (2023):20. |
入库方式： OAI收割
来源：上海药物研究所
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