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

Autor:	Thomson C; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Braybrooke E; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Colclough N; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Davies NL; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Floc'h N; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Greenwood R; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Guérot C; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Hargreaves D; Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Johnstrom P; AstraZeneca Translational Centre, Personal Healthcare and Biomarkers, AstraZeneca R&D, Karolinska Institutet, Department of Clinical Neuroscience, Karolinska University Hospital, R5:U1, Stockholm SE-171 76, Sweden., Khurana P; Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Kostomiris DH; Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Li S; Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China., Lister A; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Lorthioir O; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Martin S; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., McCoull W; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., McLean NJ; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., McWilliams L; Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Orme JP; Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Packer MJ; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Pearson S; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Swaih AM; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Tentarelli S; Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Tucker MJ; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Ward RA; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Wilkinson S; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Winlow P; Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom., Wood IL; Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Sep 28. Date of Electronic Publication: 2024 Sep 28.
DOI:	10.1021/acs.jmedchem.4c01792
Abstrakt:	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.
Databáze:	MEDLINE
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