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首页> 外文期刊>Journal of Medicinal Chemistry >Trisubstituted Imidazoles with a Rigidized Hinge Binding Motif Act As Single Digit nM Inhibitors of Clinically Relevant EGFR L858R/T790M and L858R/T790M/C797S Mutants: An Example of Target Hopping
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Trisubstituted Imidazoles with a Rigidized Hinge Binding Motif Act As Single Digit nM Inhibitors of Clinically Relevant EGFR L858R/T790M and L858R/T790M/C797S Mutants: An Example of Target Hopping

机译：具有刚性铰链结合基序的三取代咪唑，作为临床相关EGFR L858R / T790M和L858R / T790M / C797S突变体的单位数NM抑制剂：目标跳跃的一个例子

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摘要

The high genomic instability of non-small cell lung cancer tumors leads to the rapid development of resistance against promising EGFR tyrosine kinase inhibitors (TKIs). A recently detected triple mutation compromises the activity of the gold standard third-generation EGFR inhibitors. We have prepared a set of trisubstituted imidazoles with a rigidized 7-azaindole hinge binding motif as a new structural class of EGFR inhibitors by a target hopping approach from p38a MAPK inhibitor templates. On the basis of an iterative approach of docking, compound preparation, biological testing, and SAR interpretation, robust and flexible synthetic routes were established. As a result, we report two reversible inhibitors 11c1 and lie of the clinically challenging triple mutant L858R/T790M/C797S with IC50 values in the low nanomolar range. Furthermore, we developed a kinome selective irreversible inhibitor 45a with an IC50 value of 1 nM against the EGFR L858R/T790M double mutant. Target binding kinetics and metabolic stability data are included. These potent mutant EGFR inhibitors may serve as a basis for the development of structurally novel EGFR probes, tools, or candidates.
机译：非小细胞肺癌肿瘤的高基因不稳定性导致抗抗抗蛋白酶激酶抑制剂（TKIS）的抗性的快速发展。最近检测到的三重突变损害了金标准第三代EGFR抑制剂的活性。我们使用P38A MAPK抑制剂模板的目标跳跃方法制备了一组刚性的7-唑孔铰链结合基质作为新的EGFR抑制剂的新结构等级。根据对接的迭代方法，建立了复合制备，生物检测和SAR解释，强大，灵活的合成路线。结果，我们报告了两个可逆抑制剂11c1，并在低纳米摩尔范围内具有IC50值的临床挑战三重突变L858R / T790M / C797S。此外，我们开发了一种Kinome选择性不可逆抑制剂45A，其IC50值为1nm对EGFR L858R / T790M双突变体。包括目标结合动力学和代谢稳定性数据。这些有效的突变突变体EGFR抑制剂可以作为开发结构新的EGFR探针，工具或候选者的基础。

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  • 来源
    《Journal of Medicinal Chemistry》 |2017年第11期|共21页
  • 作者

    Juchum Michael; Guenther Marcel; Doering Eva; Sievers-Engler Adrian; Laemmerhofer Michael; Laufer Stefan;

  • 作者单位

    Eberhard Karls Univ Tubingen Inst Pharmaceut Sci Dept Pharmaceut Chem Morgenstelle 8 D-72076 Tubingen Germany;

    Eberhard Karls Univ Tubingen Inst Pharmaceut Sci Dept Pharmaceut Chem Morgenstelle 8 D-72076 Tubingen Germany;

    Eberhard Karls Univ Tubingen Inst Pharmaceut Sci Dept Pharmaceut Chem Morgenstelle 8 D-72076 Tubingen Germany;

    Eberhard Karls Univ Tubingen Inst Pharmaceut Sci Dept Pharmaceut Chem Morgenstelle 8 D-72076 Tubingen Germany;

    Eberhard Karls Univ Tubingen Inst Pharmaceut Sci Dept Pharmaceut Chem Morgenstelle 8 D-72076 Tubingen Germany;

    Eberhard Karls Univ Tubingen Inst Pharmaceut Sci Dept Pharmaceut Chem Morgenstelle 8 D-72076 Tubingen Germany;

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  • 正文语种 eng
  • 中图分类 药学;
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