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

  • J Med Chem. 2024 Sep 28. doi: 10.1021/acs.jmedchem.4c01792.
Clare Thomson  1 ,  Erin Braybrooke  1 ,  Nicola Colclough  1 ,  Nichola L Davies  1 ,  Nicolas Floc'h  1 ,  Ryan Greenwood  1 ,  Carine Guérot  1 ,  David Hargreaves  2 ,  Peter Johnstrom  3 ,  Puneet Khurana  2 ,  Demetrios H Kostomiris  4 ,  Songlei Li  5 ,  Andrew Lister  1 ,  Olivier Lorthioir  1 ,  Scott Martin  1 ,  William McCoull  1 ,  Neville J McLean  1 ,  Lisa McWilliams  2 ,  Jonathan P Orme  2 ,  Martin J Packer  1 ,  Stuart Pearson  1 ,  Aisha M Swaih  1 ,  Sharon Tentarelli  6 ,  Michael J Tucker  1 ,  Richard A Ward  1 ,  Stephen Wilkinson  1 ,  Poppy Winlow  2 ,  Isabel L Wood  1
Affiliations
  • 1. Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom.
  • 2. Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom.
  • 3. 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.
  • 4. Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 5. Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China.
  • 6. Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
PMID: 39340451 DOI: 10.1021/acs.jmedchem.4c01792
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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