Design, synthesis, biological evaluation and cellular imaging of imidazo[4,5- b ]pyridine derivatives as potent and selective TAM inhibitors

Tom Baladi; Jessy Aziz; Florent Dufour; Valentina Abet; Véronique Stoven; Fran?ois Radvanyi; Florent Poyer; Ting-Di Wu; Jean-Luc Guerquin-Kern; Isabelle Bernard-Pierrot; Sergio Marco Garrido; Sandrine Piguel

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Design, synthesis, biological evaluation and cellular imaging of imidazo[4,5- b ]pyridine derivatives as potent and selective TAM inhibitors

机译：咪唑[4,5- B]吡啶衍生物作为有效和选择性TAM抑制剂的设计，合成，生物学评价和细胞成像

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The TAM kinase family arises as a new effective and attractive therapeutic target for cancer therapy, autoimmune and viral diseases. A series of 2,6-disubstituted imidazo[4,5-b]pyridines were designed, synthesized and identified as highly potent TAM inhibitors. Despite remarkable structural similarities within the TAM family, compounds28and25demonstrated high activity and selectivityin vitroagainst AXL and MER, with IC50value of 0.77?nM and 9?nM respectively and a 120- to 900-fold selectivity. We also observed an unexpected nuclear localization for compound10Bb, thanks to nanoSIMS technology, which could be correlated to the absence of cytotoxicity on three different cancer cell lines being sensitive to TAM inhibition.

机译：TAM激酶家族是癌症治疗，自身免疫和病毒疾病的一种新的有效和有吸引力的治疗靶标。设计了一系列2,6-二取代的咪唑[4,5-B]吡啶，合成并鉴定为高效的TAM抑制剂。尽管TAM系列内的结构相似性显着，但化合物28和25颗致密的高活性和选择性vitroagainst AXL和MER，IC50Value分别为0.77Ω·Nm和9？Nm，选择性120-至900倍。由于纳米斯米斯技术，我们还观察到化合物10BB的意外的核定位，这可能与三种不同癌细胞系上没有细胞毒性的缺乏相关性对TAM抑制来相关。

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《Bioorganic and medicinal chemistry》 |2018年第20期|共21页
作者
Tom Baladi; Jessy Aziz; Florent Dufour; Valentina Abet; Véronique Stoven; Fran?ois Radvanyi; Florent Poyer; Ting-Di Wu; Jean-Luc Guerquin-Kern; Isabelle Bernard-Pierrot; Sergio Marco Garrido; Sandrine Piguel;
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Institut Curie PSL Research University CNRS INSERM;

Institut Curie PSL Research University CNRS INSERM;

Institut Curie PSL Research University CNRS;

Institut Curie PSL Research University CNRS INSERM;

Institut Curie PSL Research University;

Institut Curie PSL Research University CNRS;

Institut Curie PSL Research University CNRS INSERM;

Institut Curie PSL Research University CNRS INSERM;

Institut Curie PSL Research University CNRS INSERM;

Institut Curie PSL Research University CNRS;

Institut Curie PSL Research University CNRS INSERM;

Institut Curie PSL Research University CNRS INSERM;

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原文格式 PDF
正文语种 eng
中图分类药学;
关键词
Kinase inhibitors; AXL; TYRO3; MER; Imidazopyridines; NanoSIMS imaging;

机译：激酶抑制剂;AXL;TYRO3;MER;咪唑吡啶;纳米咪唑成像;

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1. Design, synthesis, biological evaluation and cellular imaging of imidazo[4,5- b ]pyridine derivatives as potent and selective TAM inhibitors [J] . Tom Baladi, Jessy Aziz, Florent Dufour, Bioorganic and medicinal chemistry . 2018,第20期

机译：咪唑[4,5- B]吡啶衍生物作为有效和选择性TAM抑制剂的设计，合成，生物学评价和细胞成像
2. Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors [J] . Li Chunpu, Ai Jing, Zhang Dengyou, ACS medicinal chemistry letters . 2015,第5期

机译：新型咪唑并[1,2-a]吡啶衍生物作为强效c-Met抑制剂的设计，合成及生物学评价
3. Aurora Isoform Selectivity: Design and Synthesis of Imidazo[4,5?b]pyridine Derivatives as Highly Selective Inhibitors of Aurora?A Kinase in Cells [J] . Vassilios Bavetsias, Amir Faisal, Simon Crumpler, Journal of Medicinal Chemistry . 2013,第22期

机译：Aurora亚型选择性：咪唑并[4,5？b]吡啶衍生物作为细胞中Aurora？A激酶的高选择性抑制剂的设计与合成
4. A highly selective cell permeable peptide inhibitor of proprotein convertase 1:design,synthesis and biological evaluation in cellular PC1-mediated proteolysis [C] . Ajoy Basak, Peter Koch, Marcel Dupelle, the International Peptide Symposium . 2001

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5. Design, synthesis, and biological evaluation of betulinic acid derivatives as potent anti-HIV-1 agents. [D] . Qian, Keduo. 2008

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6. Design of new disubstituted imidazo12-bpyridazine derivatives as selective Haspin inhibitors. Synthesis binding mode and anticancer biological evaluation [O] . Jonathan Elie, Omid Feizbakhsh, Nathalie Desban, 2020

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7. Design of new disubstituted imidazo1,2-bpyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation [O] . Jonathan Elie, Omid Feizbakhsh, Nathalie Desban, 2020

机译：新的二取代的咪唑（吡啶嗪衍生物为选择性HAPIN抑制剂的设计。合成，结合模式和抗癌生物学评估

Design, synthesis, biological evaluation and cellular imaging of imidazo[4,5- b ]pyridine derivatives as potent and selective TAM inhibitors

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