AZ14289671 is a highly selective and blood-brain barrier penetrant irreversible TKI that targets EGFRExon20 insertions
Current clinical therapeutics against non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (EGFRExon20Ins) mutations yield limited responses particularly against brain metastases; therefore, there is a need for an effective tyrosine kinase inhibitor (TKI). AZ14289671 is an oral, potent, irreversible, selective, and blood-brain barrier penetrant TKI targeting EGFRExon20Ins mutations while sparing wild-type (WT) EGFR. Preclinical assessments using cell lines, cell line-derived xenograft, and patient-derived xenograft models harboring EGFRExon20Ins demonstrate that AZ14289671 exhibits strong signaling pathway inhibition and highly sustained tumor regression against multiple EGFRExon20Ins, whereas its activity against WT is minimal. Additionally, AZ14289671 can cross the blood-brain barrier. This has the potential to improve outcomes of NSCLC patients with EGFRExon20Ins.
Authors
- Sabina Cosulich (ORCID: https://orcid.org/0000-0001-9666-0510)
- Aaron Smith (ORCID: https://orcid.org/0000-0003-3768-8550)
- Nicolas Floc’h
- Benjamin Phillips (ORCID: https://orcid.org/0000-0001-9161-8903)
- Nicola Colclough
- David Hargreaves (ORCID: https://orcid.org/0000-0003-4441-0039)
- Peter Johnström (ORCID: https://orcid.org/0009-0007-9725-9172)
- 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)
- Lisa McWilliams (ORCID: https://orcid.org/0000-0002-0613-8647)
- Vikki Flemington
- Clare Thomson (ORCID: https://orcid.org/0000-0003-3160-1397)
- Sara Talbot
- Colleen S. Deane (ORCID: https://orcid.org/0000-0002-2281-6479)
- Jonathan P. Orme
- Adriana Savoca (ORCID: https://orcid.org/0000-0002-8031-8726)
- Paul R. J. Davey (ORCID: https://orcid.org/0000-0001-7269-2526)
- Aisha M. Swaih
- Daniel O’Neill (ORCID: https://orcid.org/0009-0006-3424-7214)
- Hannah Thorpe (ORCID: https://orcid.org/0000-0002-8096-4381)
- Catarina Felisberto-Rodrigues
- Marianne Enget
- Veronika Radeva
Institutions
- The Francis Crick Institute (GB)
- AstraZeneca (South Korea) (KR)
- AstraZeneca (Australia) (AU)
- AstraZeneca (Sweden) (SE)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-08-25
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102305
- Primary Topic
- Lung Cancer Treatments and Mutations
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- AstraZeneca