Synthesis and Biological Evaluation of Oxopyrido[2,3-d] Pyrimidine-7-ones Derivatives as Covalent L85812/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors
文献类型：期刊论文
| 作者 | Niu, Ao1; Wang, Yang2; Yang, Yushe4 ; Wei, Jianhai3; Ding, Jian4; Chen, Yi4; Tong, Linjiang4; Xie, Hua4
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| 刊名 | LETTERS IN DRUG DESIGN & DISCOVERY
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| 出版日期 | 2019 |
| 卷号 | 16期号:8页码:826-834 |
| 关键词 | Non-small cell lung cancer irreversible inhibitors EGFR(T79014)( )mutant anti-tumor xenograft model cell proliferation |
| ISSN号 | 1570-1808 |
| DOI | 10.2174/1570180815666180523090558 |
| 通讯作者 | Yang, Yushe(ysyang@simm.ac.cn) |
| 英文摘要 | Background: None small cell cancer (NSCLC) is one of the most common cancer around the globe. First generation EGFR-TKI such as gefitinib and erlotinib are now documentated a prolonged PFS in NSCLC patients with EGFR activating mutation. However, upon continuous treatment, patients become resistant due toCEE T790M mutation in most cases.Second generation covalent EGFR inhibitors like afatinib have a moderate inhibition to EGFRT790M in preclinical models,but it is lacking efficacy in the clinical use for patients with T790M mutation due to the dose-limiting EGFRWT-driven toxicities.Third generation EGFR inhibitors have the potential to overcome EGFRT790M resistance mutations while reducing EGFRWT-driven toxicities and are now under active research. Methods: We took compound 6 as our lead compound. We focused on structural modifications around the hydrophile side chain, the linker, and the Micheal addition receptor moiety of AMG. A novel series of Oxopyrido[2,3-d]pyrimidine-7-ones derivatives have been designed and synthesized. Their kinase inhibition activity against EGFRwT and EGFRL858R/T790m were tested by ELISA assays. SRB test was used for cellular anti-proliferation evaluation. Results: A total of 21 novel Oxopyrido[2,3-d]pyrimidine-7-ones derivatives have been designed and synthesized. The compounds were characterized with H-1-NMR and FIRMS. Their structure-activity relationships have been preliminaryly investigated. As a result, compound 7k showed comparable activity in kinase inhibition assay and cell growth inhibition assay with our lead compound 6. Higher activity and selectivity over EGFRWT were observed in the in vitro antitumour assay comparing compound 7k to AZD-9291. Compound 7a exhibited higher selectivity over EGFRWT in kinase inhibition assay, but poor cell inhibition to NCI-1975 cell line. The in vivo pharmacokinetic studies in rats showed that compound 9a exhibited improved pharmacokinetic profiles comparing to 6. Compound 9a was also efficacious in an NCI-H1975 murine xenograft model 30 mg/kg QD. Conclusion: Compound 9a has a potent kinase inhibition to EGFRT790m( )and has a high selectivity over EGFRWT. It's also efficacious in an in vivo pharmacodynamic evaluation assay. Significant advantages were observed in pharmacokinetic evaluation comparing 9a to 6, which provide us a reference to further drug design and research. |
| WOS关键词 | LUNG-CANCER ; KINASE INHIBITORS ; MUTATIONS ; RESISTANCE ; AZD9291 |
| 资助项目 | Personalized MedicinesMolecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020335] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000480359800001 |
| 出版者 | BENTHAM SCIENCE PUBL LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/288996]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Yang, Yushe |
| 作者单位 | 1.China Pharmaceut Univ, Sch Pharm, Nanjing 210009, Jiangsu, Peoples R China 2.Univ Sci & Technol China, Nano Sci & Technol Inst, Suzhou 215123, Peoples R China 3.East China Normal Univ, Sch Chem & Mol Engn, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, North Zhongshan Rd 3663, Shanghai, Peoples R China 4.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 | Niu, Ao,Wang, Yang,Yang, Yushe,et al. Synthesis and Biological Evaluation of Oxopyrido[2,3-d] Pyrimidine-7-ones Derivatives as Covalent L85812/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors[J]. LETTERS IN DRUG DESIGN & DISCOVERY,2019,16(8):826-834. |
| APA | Niu, Ao.,Wang, Yang.,Yang, Yushe.,Wei, Jianhai.,Ding, Jian.,...&Xie, Hua.(2019).Synthesis and Biological Evaluation of Oxopyrido[2,3-d] Pyrimidine-7-ones Derivatives as Covalent L85812/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors.LETTERS IN DRUG DESIGN & DISCOVERY,16(8),826-834. |
| MLA | Niu, Ao,et al."Synthesis and Biological Evaluation of Oxopyrido[2,3-d] Pyrimidine-7-ones Derivatives as Covalent L85812/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors".LETTERS IN DRUG DESIGN & DISCOVERY 16.8(2019):826-834. |
入库方式： OAI收割
来源：上海药物研究所
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