- Novel pyrimido-heterocyclic compound and preparation method and application thereof
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The invention discloses a novel pyrimido-heterocyclic compound and a preparation method and application thereof. The structure of the pyrimido-heterocyclic compound disclosed by the invention is as shown in a general formula I, and the definitions of all substituents are described in the specification and claims. The pyrimido-heterocyclic compound disclosed by the invention has much better inhibitory activity and selectivity for double-mutant EGFR kinase than the existing AZD-9291, can be used for preparing anti-tumor drugs, and overcomes the defect of drug tolerance of the first generation ofEGFR inhibitor.
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Paragraph 0081; 0083; 0084; 0085
(2019/02/19)
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- Synthesis and biological evaluation of oxopyrido[2,3-d] pyrimidine-7- ones derivatives as covalent L858R/T790M mutant selective Epidermal Growth Factor Receptor (EGFR) inhibitors
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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 1H-NMR and HRMS. Their structureactivity 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.
- Niu, Ao,Wang, Yang,Yang, Yushe,Wei, Jianhai,Ding, Jian,Chen, Yi,Tong, Linjiang,Xie, Hua
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p. 826 - 834
(2019/10/28)
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- A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFRL858R/T790Mmutant with improved pharmacokinetic properties
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Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFRT790Minhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFRL858R/T790Mkinase and inhibited the proliferation of H1975?cells with IC50values of 2.0?nM and 40?nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERK in NCI[sbnd]H1975?cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.
- Yu, Lei,Huang, Minhao,Xu, Tianfeng,Tong, Linjiang,Yan, Xiao-e,Zhang, Zhang,Xu, Yong,Yun, Caihong,Xie, Hua,Ding, Ke,Lu, Xiaoyun
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p. 1107 - 1117
(2016/12/30)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
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Paragraph 0161; 0162; 0178
(2015/10/05)
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- Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors
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In nonsmall cell lung cancer (NSCLC), the threonine790-methionine790 (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound 24 which potently inhibits gefitinib-resistant EGFRL858R,T790M with 100-fold selectivity over wild-type EGFR. Compound 24 displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFRL858R,T790M driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.
- Wurz, Ryan P.,Pettus, Liping H.,Ashton, Kate,Brown, James,Chen, Jian Jeffrey,Herberich, Brad,Hong, Fang-Tsao,Hu-Harrington, Essa,Nguyen, Tom,St. Jean, David J.,Tadesse, Seifu,Bauer, David,Kubryk, Michele,Zhan, Jinghui,Cooke, Keegan,Mitchell, Petia,Andrews, Kristin L.,Hsieh, Faye,Hickman, Dean,Kalyanaraman, Nataraj,Wu, Tian,Reid, Darren L.,Lobenhofer, Edward K.,Andrews, Dina A.,Everds, Nancy,Guzman, Roberto,Parsons, Andrew T.,Hedley, Simon J.,Tedrow, Jason,Thiel, Oliver R.,Potter, Matthew,Radinsky, Robert,Beltran, Pedro J.,Tasker, Andrew S.
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supporting information
p. 987 - 992
(2015/09/22)
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- C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFRT790M mutant
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The development of specific kinase inhibitors has been a long-standing challenge in chemical biology and drug discovery. We have successfully discovered a series of C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific inhibitors against the clinical resistance-related EGFRT790M mutant. One of the most promising compounds, 9f, tightly binds to the EGFRT790M mutant and strongly inhibits its enzymatic function with an IC50 value of 0.80 nM, and displays an extraordinary target specificity with S(35) and S(10) selectivity scores of 0.005 and 0.000, respectively, in a kinase selectivity profiling study against 456 different kinases at 100 nM. The compound also selectively suppresses the proliferation of EGFRT790M mutated H1975 NSCLC cells with an IC50 value of 2.80 nM, but is significantly less toxic to cells with wild-type EGFR. Compound 9f may serve as a promising lead compound for drug discovery overcoming the acquired resistance of NSCLC patients without adverse toxicities.
- Xu, Tianfeng,Peng, Ting,Ren, Xiaomei,Zhang, Lianwen,Yu, Lei,Luo, Jinfeng,Zhang, Zhang,Tu, Zhengchao,Tong, Linjiang,Huang, Zhaoru,Lu, Xiaoyun,Geng, Meiyu,Xie, Hua,Ding, Jian,Ding, Ke
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supporting information
p. 1693 - 1697
(2015/09/21)
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- HETEROARYL COMPOUNDS AND USES THEREOF
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The present invention provides inhibitors of protein kinases of formula I-a and I-b, pharmaceutically acceptable compositions thereof, and methods of using the same.
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Page/Page column 276
(2010/01/30)
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