Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations
Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether <b>23</b> and biaryl <b>36</b> as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne <b>5</b> which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CL<sub>int</sub> compounds while maintaining a WT selectivity margin. During optimization, aldehyde oxidase (AO) metabolism was identified as a human clearance risk, and through SAR exploration, lower AO metabolism was achieved. Potency and WT margin were optimized across a range of Ex20Ins mutants including the potential acquired resistance T790M mutant and efficacy demonstrated in an LXF2478 Ex20Ins ASV model with margin to EGFR WT in vivo.
Authors
- Stuart E. Pearson
- Andrew Lister
- Chunli Wang (ORCID: https://orcid.org/0000-0003-2781-0401)
- Erin Braybrooke
- Ryan Greenwood
- Thomas A. Hunt (ORCID: https://orcid.org/0000-0003-1227-8862)
- Joanne Wilson (ORCID: https://orcid.org/0000-0002-3778-1918)
- Demetrios H. Kostomiris
- Sabina Cosulich (ORCID: https://orcid.org/0000-0001-9666-0510)
- S.P. Stokes
- Nicolas Floc’h
- Nichola L. Davies (ORCID: https://orcid.org/0000-0003-4591-8264)
- Scott Martin
- Neville McLean
- Jason G. Kettle (ORCID: https://orcid.org/0000-0001-7373-0758)
- Nicola Colclough
- Miguel A. Cortés González (ORCID: https://orcid.org/0000-0003-4299-8860)
- David Hargreaves (ORCID: https://orcid.org/0000-0003-4441-0039)
- Darren McKerrecher
- Peter Johnström (ORCID: https://orcid.org/0009-0007-9725-9172)
- Mikhail Kondrashov (ORCID: https://orcid.org/0000-0002-8033-3942)
- J. Willem M. Nissink (ORCID: https://orcid.org/0000-0003-2572-9140)
- Peng Huang (ORCID: https://orcid.org/0000-0003-0620-0911)
- Ya‐Wen Yang (ORCID: https://orcid.org/0000-0001-6330-6830)
- Songlei Li
- Martin J. Packer (ORCID: https://orcid.org/0000-0002-2457-2703)
- Magnus Schou (ORCID: https://orcid.org/0000-0002-4314-2418)
- William McCoull (ORCID: https://orcid.org/0000-0002-2977-1744)
- Lina Qin (ORCID: https://orcid.org/0000-0002-6625-0198)
- Christina Chan (ORCID: https://orcid.org/0000-0002-6031-0698)
- Clare Thomson (ORCID: https://orcid.org/0000-0003-3160-1397)
- Sara Talbot
- Jonathan P. Orme
- Richard A. Ward (ORCID: https://orcid.org/0000-0002-2310-9477)
- Adriana Savoca (ORCID: https://orcid.org/0000-0002-8031-8726)
- Aisha M. Swaih
- Michael Tucker (ORCID: https://orcid.org/0000-0002-4818-4684)
- Tony Johnson
- Paige Orwig
- Catarina Felisberto-Rodrigues
- Emma Wadforth
Institutions
- Stockholm County Council (SE)
- Karolinska Institutet (SE)
- AstraZeneca (Brazil) (BR)
- Université Bourgogne Franche-Comté (FR)
- AstraZeneca (Poland) (PL)
- AstraZeneca (Sweden) (SE)
- AstraZeneca (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-01-27
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02811
- Citations
- 5
- Primary Topic
- Lung Cancer Treatments and Mutations
- Type
- article
- Field-Weighted Citation Impact
- 7.59