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Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-09-30 , DOI: 10.1021/acs.jmedchem.2c00893
Ulrike Obst-Sander 1 , Antonio Ricci 1 , Bernd Kuhn 1 , Thomas Friess 2 , Philipp Koldewey 1 , Andreas Kuglstatter 1 , David Hewings 1 , Annick Goergler 1 , Sandra Steiner 1 , Daniel Rueher 1 , Marie-Paule Imhoff 1 , Noemi Raschetti 1 , Hans-Peter Marty 1 , Aline Dietzig 3 , Caroline Rynn 4 , Andreas Ehler 1 , Dominique Burger 1 , Martin Kornacker 5 , Jeannine Petrig Schaffland 1 , Frank Herting 2 , William Pao 6 , James R Bischoff 3 , Bruno Martoglio 3 , Yvonne Alice Nagel 3 , Georg Jaeschke 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-09-30 , DOI: 10.1021/acs.jmedchem.2c00893
Ulrike Obst-Sander 1 , Antonio Ricci 1 , Bernd Kuhn 1 , Thomas Friess 2 , Philipp Koldewey 1 , Andreas Kuglstatter 1 , David Hewings 1 , Annick Goergler 1 , Sandra Steiner 1 , Daniel Rueher 1 , Marie-Paule Imhoff 1 , Noemi Raschetti 1 , Hans-Peter Marty 1 , Aline Dietzig 3 , Caroline Rynn 4 , Andreas Ehler 1 , Dominique Burger 1 , Martin Kornacker 5 , Jeannine Petrig Schaffland 1 , Frank Herting 2 , William Pao 6 , James R Bischoff 3 , Bruno Martoglio 3 , Yvonne Alice Nagel 3 , Georg Jaeschke 1
Affiliation
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Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFRC797S mutation remains a highly unmet need in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present the discovery of the allosteric EGFR inhibitor 57, a novel fourth-generation inhibitor to overcome EGFRC797S-mediated resistance in patients harboring the activating EGFRL858R mutation. 57 exhibits an improved potency compared to previous allosteric EGFR inhibitors. To our knowledge, 57 is the first allosteric EGFR inhibitor that demonstrates robust tumor regression in a mutant EGFRL858R/C797S tumor model. Additionally, 57 is active in an H1975 EGFRL858R/T790M NSCLC xenograft model and shows superior efficacy in combination with osimertinib compared to the single agents. Our data highlight the potential of 57 as a single agent against EGFRL858R/C797S and EGFRL858R/T790M/C797S and as combination therapy for EGFRL858R- and EGFRL858R/T790M-driven NSCLC.
中文翻译：
发现新型变构 EGFR L858R 抑制剂作为单药或与奥希替尼联用治疗非小细胞肺癌
在 EGFR 驱动的非小细胞肺癌 (NSCLC) 中，通过 EGFR C797S突变解决对奥希替尼等第三代 EGFR TKI 的耐药性仍然是一个高度未满足的需求。在此，我们介绍了变构 EGFR 抑制剂57的发现，这是一种新型的第四代抑制剂，可克服携带激活 EGFR L858R突变的患者的 EGFR C797S介导的耐药性。与以前的别构 EGFR 抑制剂相比，57显示出改进的效力。据我们所知，57是第一个在突变 EGFR L858R/C797S肿瘤模型中表现出强大的肿瘤消退的变构 EGFR 抑制剂。此外，57在 H1975 EGFR L858R/T790M NSCLC 异种移植模型中具有活性，并且与单药相比，与奥希替尼联用显示出更好的疗效。我们的数据强调了57作为针对 EGFR L858R/C797S和 EGFR L858R/T790M/C797S的单一药物以及作为 EGFR L858R 和 EGFR L858R/T790M 驱动的 NSCLC 的联合疗法的潜力。
更新日期：2022-09-30
中文翻译：
发现新型变构 EGFR L858R 抑制剂作为单药或与奥希替尼联用治疗非小细胞肺癌
在 EGFR 驱动的非小细胞肺癌 (NSCLC) 中，通过 EGFR C797S突变解决对奥希替尼等第三代 EGFR TKI 的耐药性仍然是一个高度未满足的需求。在此，我们介绍了变构 EGFR 抑制剂57的发现，这是一种新型的第四代抑制剂，可克服携带激活 EGFR L858R突变的患者的 EGFR C797S介导的耐药性。与以前的别构 EGFR 抑制剂相比，57显示出改进的效力。据我们所知，57是第一个在突变 EGFR L858R/C797S肿瘤模型中表现出强大的肿瘤消退的变构 EGFR 抑制剂。此外，57在 H1975 EGFR L858R/T790M NSCLC 异种移植模型中具有活性，并且与单药相比，与奥希替尼联用显示出更好的疗效。我们的数据强调了57作为针对 EGFR L858R/C797S和 EGFR L858R/T790M/C797S的单一药物以及作为 EGFR L858R 和 EGFR L858R/T790M 驱动的 NSCLC 的联合疗法的潜力。
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