Optimization of Potent, Efficacious, Selective and Blood–Brain Barrier Penetrating Inhibitors Targeting EGFR Exon20 Insertion Mutations

IF 5.3 2区材料科学 Q2 MATERIALS SCIENCE, MULTIDISCIPLINARY

ACS Applied Nano Materials Pub Date : 2024-09-28 DOI:10.1021/acs.jmedchem.4c01792

Clare Thomson, Erin Braybrooke, Nicola Colclough, Nichola L. Davies, Nicolas Floc’h, Ryan Greenwood, Carine Guérot, David Hargreaves, Peter Johnstrom, Puneet Khurana, Demetrios H. Kostomiris, Songlei Li, Andrew Lister, Olivier Lorthioir, Scott Martin, William McCoull, Neville J. McLean, Lisa McWilliams, Jonathan P. Orme, Martin J. Packer, Stuart Pearson, Aisha M. Swaih, Sharon Tentarelli, Michael J. Tucker, Richard A. Ward, Stephen Wilkinson, Poppy Winlow, Isabel L. Wood

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Abstract

Herein, we report the optimization of a series of epidermal growth factor receptor (EGFR) Exon20 insertion (Ex20Ins) inhibitors using structure-based drug design (SBDD), leading to the discovery of compound 28, a potent and wild type selective molecule, which demonstrates efficacy in multiple EGFR Ex20Ins xenograft models and blood–brain barrier penetration in preclinical species. Building on our earlier discovery of an in vivo probe, SBDD was used to design a novel bicyclic core with a lower molecular weight to facilitate blood–brain barrier penetration. Further optimization including strategic linker replacement and diversification of the ring system interacting with the c-helix enabled photolytic and metabolic stability improvements. Together with refinement of molecular properties important for achieving high brain exposure, including molecular weight, H-bonding, and polarity, 28 was identified.

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优化针对表皮生长因子受体外显子 20 插入突变的强效、有效、选择性和血脑屏障穿透性抑制剂

在本文中，我们报告了利用基于结构的药物设计（SBDD）对一系列表皮生长因子受体（EGFR）Exon20 插入（Ex20Ins）抑制剂进行优化的结果，最终发现了化合物 28，这是一种强效的野生型选择性分子，在多种 EGFR Ex20Ins 异种移植模型中显示出疗效，并在临床前物种中显示出血脑屏障穿透性。在早先发现的体内探针的基础上，我们利用 SBDD 设计了一种新型双环核心，分子量较低，有利于血脑屏障穿透。通过进一步优化，包括策略性地更换连接体以及使与 c-螺旋相互作用的环系统多样化，光解稳定性和代谢稳定性都得到了提高。此外，还完善了对实现高脑部暴露率非常重要的分子特性，包括分子量、H 键和极性。

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来源期刊

ACS Applied Nano Materials Multiple-

CiteScore

8.30

自引率

3.40%

发文量

1601

期刊介绍： ACS Applied Nano Materials is an interdisciplinary journal publishing original research covering all aspects of engineering, chemistry, physics and biology relevant to applications of nanomaterials. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrate knowledge in the areas of materials, engineering, physics, bioscience, and chemistry into important applications of nanomaterials.