AZ14289671 is a highly selective and blood-brain barrier penetrant irreversible TKI that targets EGFRExon20 insertions

  • Cell Rep Med. 2025 Sep 16;6(9):102305. doi: 10.1016/j.xcrm.2025.102305.
Aisha M Swaih  1 ,  Sara Talbot  1 ,  Adriana Savoca  2 ,  Hannah Thorpe  1 ,  Vikki Flemington  1 ,  Benjamin Phillips  3 ,  Nicola Colclough  4 ,  William McCoull  5 ,  Veronika Radeva  1 ,  David Hargreaves  3 ,  Martin J Packer  5 ,  Catarina Felisberto-Rodrigues  3 ,  Clare Thomson  5 ,  Jonathan P Orme  3 ,  Carly Deane  4 ,  Aaron Smith  4 ,  Peter Johnström  6 ,  Magnus Schou  6 ,  Lisa McWilliams  3 ,  Paul Davey  5 ,  Marianne Enget  5 ,  Daniel O'Neill  3 ,  Sabina Cosulich  7 ,  Nicolas Floc'h  8
Affiliations
  • 1. Bioscience, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, UK.
  • 2. Clinical Pharmacology and Safety Sciences, BioPharmaceutical R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, UK.
  • 3. Discovery Sciences, BioPharmaceutical R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, UK.
  • 4. DMPK, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, UK.
  • 5. Chemistry, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, UK.
  • 6. PET Science Centre, Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Stockholm 171 76, Sweden.
  • 7. Early Oncology Development, Oncology R&D AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, UK.
  • 8. Bioscience, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, UK. Electronic address: [email protected].
PMID: 40858103 DOI: 10.1016/j.xcrm.2025.102305
Abstract

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.

Keywords
EGFR; NSCLC; exon 20 insertions; small molecule inhibitor.
Products