Optimization of Potent, Efficacious, Selective and Blood–Brain Barrier Penetrating Inhibitors Targeting EGFR Exon20 Insertion Mutations
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 <b>28</b>, 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 <i>in vivo</i> 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, <b>28</b> was identified.
Authors
- Stuart E. Pearson
- Andrew Lister
- Erin Braybrooke
- Ryan Greenwood
- Demetrios H. Kostomiris
- Nicolas Floc’h
- Nichola L. Davies (ORCID: https://orcid.org/0000-0003-4591-8264)
- Scott Martin
- Neville McLean
- Puneet Khurana
- Nicola Colclough
- David Hargreaves (ORCID: https://orcid.org/0000-0003-4441-0039)
- Peter Johnström (ORCID: https://orcid.org/0009-0007-9725-9172)
- Songlei Li
- Martin J. Packer (ORCID: https://orcid.org/0000-0002-2457-2703)
- William McCoull (ORCID: https://orcid.org/0000-0002-2977-1744)
- Lisa McWilliams (ORCID: https://orcid.org/0000-0002-0613-8647)
- Sharon Tentarelli (ORCID: https://orcid.org/0000-0003-2968-8120)
- Clare Thomson (ORCID: https://orcid.org/0000-0003-3160-1397)
- Olivier Lorthioir (ORCID: https://orcid.org/0000-0003-4191-4522)
- Carine Guérot
- Jonathan P. Orme
- Richard A. Ward (ORCID: https://orcid.org/0000-0002-2310-9477)
- Stephen Wilkinson (ORCID: https://orcid.org/0000-0003-0204-013X)
- Poppy Winlow
- Aisha M. Swaih
- Michael Tucker (ORCID: https://orcid.org/0000-0002-4818-4684)
- Isabel L. Wood
Institutions
- AstraZeneca (United Kingdom) (GB)
- Karolinska University Hospital (SE)
- Karolinska Institutet (SE)
- Université Bourgogne Franche-Comté (FR)
- AstraZeneca (Sweden) (SE)
- AstraZeneca (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-28
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01792
- Citations
- 3
- Primary Topic
- Lung Cancer Treatments and Mutations
- Type
- article
- Field-Weighted Citation Impact
- 1.26