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Design, Synthesis, and Evaluation of (R)-8-((Tetrahydrofuran-2-yl)methyl)pyrido[2,3-d]pyrimidin-7-ones as Novel Selective ACK1 Inhibitors to Combat Acquired Resistance to the Third-Generation EGFR Inhibitor

文献类型：期刊论文

作者Li, Qian1; Zhang, Tao; Song, Peiran3; Tong, Linjiang2; Feng, Fang2; Guo, Jing1; Zhou, Yang1; Xie, Hua2,3; Lu, Xiaoyun1
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-05-03
页码17
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c00319
通讯作者Xie, Hua(hxie@simm.ac.cn) ; Lu, Xiaoyun(luxy2016@jnu.edu.cn)
英文摘要Activated Cdc42-associated kinase 1 (ACK1) alterations have been considered to mediate bypass acquired resistance to the third-generation EGFR inhibitors (ASK120067 and osimertinib) in NSCLC. Despite many efforts to develop ACK1 small molecule inhibitors, no selective inhibitors have entered clinical trials. We used structure-based drug design to obtain a series of (R)-8-((tetrahydrofuran-2-yl)methyl)pyrido [2,3-d]pyrimidin-7-ones as novel selective ACK1 inhibitors. One of the representative compounds, 10zi, potently inhibited ACK1 kinase with an IC50 of 2.1 nM, while sparing SRC kinase (IC50 = 218.7 nM). Further, 10zi displayed good kinome selectivity in a profiling of 468 kinases. In the ASK120067-resistant lung cancer cell line (67R), 10zi dose-dependently inhibited the phosphorylation of ACK1 and downstream AKT pathway and showed a strong synergistic anti-tumor effect in combination with ASK120067 in vitro. Additionally, 10zi also exhibited reasonable PK profiles with an oral bioavailability of 19.8% at the dose of 10 mg/kg, which provided a promising lead for further development of new anticancer drugs.
WOS关键词ANDROGEN RECEPTOR ; PHOSPHORYLATION ; OPTIMIZATION ; DISCOVERY
资助项目National Natural Science Foundation of China[82204182] ; National Natural Science Foundation of China[82273763] ; International Cooperation Project of Guang-dong Science and Technology Program[2022A0505050045] ; Natural Science Foundation of Guangdong Province[2022A1515011939] ; Open Project of State Key Laboratory of Respiratory Disease[SKLRD-OP-202313] ; Wang Kuancheng Young Scholar of Jinan University
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000986462000001
源URL[http://119.78.100.183/handle/2S10ELR8/306508]  
专题新药研究国家重点实验室
通讯作者Xie, Hua; Lu, Xiaoyun
作者单位1.Jinan Univ, Sch Pharm, Int Cooperat Lab Tradit Chinese Med Modernizat & I, Guangzhou City Key Lab Precis Chem Drug Dev,Minist, Guangzhou 510632, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
推荐引用方式
GB/T 7714		 Li, Qian,Zhang, Tao,Song, Peiran,et al. Design, Synthesis, and Evaluation of (R)-8-((Tetrahydrofuran-2-yl)methyl)pyrido[2,3-d]pyrimidin-7-ones as Novel Selective ACK1 Inhibitors to Combat Acquired Resistance to the Third-Generation EGFR Inhibitor[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023:17.
APA Li, Qian.,Zhang, Tao.,Song, Peiran.,Tong, Linjiang.,Feng, Fang.,...&Lu, Xiaoyun.(2023).Design, Synthesis, and Evaluation of (R)-8-((Tetrahydrofuran-2-yl)methyl)pyrido[2,3-d]pyrimidin-7-ones as Novel Selective ACK1 Inhibitors to Combat Acquired Resistance to the Third-Generation EGFR Inhibitor.JOURNAL OF MEDICINAL CHEMISTRY,17.
MLA Li, Qian,et al."Design, Synthesis, and Evaluation of (R)-8-((Tetrahydrofuran-2-yl)methyl)pyrido[2,3-d]pyrimidin-7-ones as Novel Selective ACK1 Inhibitors to Combat Acquired Resistance to the Third-Generation EGFR Inhibitor".JOURNAL OF MEDICINAL CHEMISTRY (2023):17.

入库方式： OAI收割

来源：上海药物研究所

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