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

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168151
    EGFR Inhibitor