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Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-11-13 , DOI: 10.1021/acs.jmedchem.9b01169 Harald Engelhardt 1 , Dietrich Böse 1 , Mark Petronczki 1 , Dirk Scharn 1 , Gerd Bader 1 , Anke Baum 1 , Andreas Bergner 1 , Eugene Chong 2 , Sandra Döbel 1 , Georg Egger 1 , Christian Engelhardt 1 , Peter Ettmayer 1 , Julian E Fuchs 1 , Thomas Gerstberger 1 , Nina Gonnella 2 , Andreas Grimm 1 , Elisabeth Grondal 1 , Nizar Haddad 2 , Barbara Hopfgartner 1 , Roland Kousek 1 , Mariusz Krawiec 2 , Monika Kriz 1 , Lyne Lamarre 1 , Joyce Leung 2 , Moriz Mayer 1 , Nitinchandra D Patel 2 , Biljana Peric Simov 1 , Jonathan T Reeves 2 , Renate Schnitzer 1 , Andreas Schrenk 1 , Bernadette Sharps 1 , Flavio Solca 1 , Heinz Stadtmüller 1 , Zhulin Tan 2 , Tobias Wunberg 1 , Andreas Zoephel 1 , Darryl B McConnell 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-11-13 , DOI: 10.1021/acs.jmedchem.9b01169 Harald Engelhardt 1 , Dietrich Böse 1 , Mark Petronczki 1 , Dirk Scharn 1 , Gerd Bader 1 , Anke Baum 1 , Andreas Bergner 1 , Eugene Chong 2 , Sandra Döbel 1 , Georg Egger 1 , Christian Engelhardt 1 , Peter Ettmayer 1 , Julian E Fuchs 1 , Thomas Gerstberger 1 , Nina Gonnella 2 , Andreas Grimm 1 , Elisabeth Grondal 1 , Nizar Haddad 2 , Barbara Hopfgartner 1 , Roland Kousek 1 , Mariusz Krawiec 2 , Monika Kriz 1 , Lyne Lamarre 1 , Joyce Leung 2 , Moriz Mayer 1 , Nitinchandra D Patel 2 , Biljana Peric Simov 1 , Jonathan T Reeves 2 , Renate Schnitzer 1 , Andreas Schrenk 1 , Bernadette Sharps 1 , Flavio Solca 1 , Heinz Stadtmüller 1 , Zhulin Tan 2 , Tobias Wunberg 1 , Andreas Zoephel 1 , Darryl B McConnell 1
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The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of BI-4020, which is a noncovalent, wild-type EGFR sparing, macrocyclic TKI. BI-4020 potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFRdel19 T790M C797S xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.
中文翻译：
开始选择性和刚性研究：发现下一代EGFR酪氨酸激酶抑制剂的途径。
表皮生长因子受体（EGFR）带有激活突变（例如del19或L858R）时，在一部分肺肿瘤中起致癌作用。尽管肿瘤对酪氨酸激酶抑制剂（TKIs）的反应伴随着明显的肿瘤缩小，但这种反应通常并不持久。大多数患者在治疗后两年内复发，通常是由于获得了赋予TKI耐药性的EGFR激酶结构域额外突变。至关重要的是，目前批准的EGFR TKIs不能再抑制同时具有T790M和C797S两个抗性突变的致癌EGFR。在这里，我们描述了BI-4020的发现，BI-4020是一种非共价的野生型EGFR节约型大环TKI。BI-4020在交叉抗性EGFR del19 T790M C797S异种移植模型中，有效抑制上述EGFR变体并诱导肿瘤消退。关键在于鉴定高选择性但中等效力的苯并咪唑，然后通过大环化将分子完全硬化。
更新日期：2019-11-14
中文翻译：
开始选择性和刚性研究：发现下一代EGFR酪氨酸激酶抑制剂的途径。
表皮生长因子受体（EGFR）带有激活突变（例如del19或L858R）时，在一部分肺肿瘤中起致癌作用。尽管肿瘤对酪氨酸激酶抑制剂（TKIs）的反应伴随着明显的肿瘤缩小，但这种反应通常并不持久。大多数患者在治疗后两年内复发，通常是由于获得了赋予TKI耐药性的EGFR激酶结构域额外突变。至关重要的是，目前批准的EGFR TKIs不能再抑制同时具有T790M和C797S两个抗性突变的致癌EGFR。在这里，我们描述了BI-4020的发现，BI-4020是一种非共价的野生型EGFR节约型大环TKI。BI-4020在交叉抗性EGFR del19 T790M C797S异种移植模型中，有效抑制上述EGFR变体并诱导肿瘤消退。关键在于鉴定高选择性但中等效力的苯并咪唑，然后通过大环化将分子完全硬化。
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