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Peer-reviewedCC BY 4.0Molecular Cancer Therapeutics

BLU-451, a CNS-Active, Potent, and Selective Small-Molecule Inhibitor against Uncommon EGFR Mutations

  • Yves A. Millet1
  • Alexander I. Spira2
  • Christina S. Baik3
  • Min Hee Hong4
  • Elaine Shum5
  • Jyoti D. Patel6
  • Danny Nguyen7
  • Pasi A. Jänne8
  • Zofia Piotrowska9
  • Natasha B. Leighl10
  • Shingo Matsumoto11
  • Lova Sun12
10 more authors
  • Tsung-Ying Yang13
  • Tatsuya Yoshida14
  • Monique B. Nilsson15
  • John V. Heymach15
  • Brion W. Murray1
  • Jeffrey Keats1
  • Stephanie Lee1
  • John Hsieh1
  • Alena Zalutskaya1
  • Xiuning Le15
15 affiliations
  1. 1Blueprint Medicines Corporation, Cambridge, Massachusetts.
  2. 2Virginia Cancer Specialists Research Institute, Fairfax, Virginia.
  3. 3Division of Hematology and Oncology, University of Washington School of Medicine, Seattle, Washington.
  4. 4Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
  5. 5NYU Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, New York.
  6. 6Tempus AI, Chicago, Illinois.
  7. 7Department of Medical Oncology and Therapeutics Research, City of Hope, Irvine, California.
  8. 8Dana-Farber Cancer Institute, Boston, Massachusetts.
  9. 9Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
  10. 10Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Canada.
  11. 11Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
  12. 12Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
  13. 13Department of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
  14. 14Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
  15. 15Department of Thoracic-Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Abstract

BLU-451 is a potent and selective tyrosine kinase inhibitor designed to target uncommon epidermal growth factor receptor (EGFR) mutations, spare wild-type (WT) EGFR, and be active in the central nervous system (CNS). In vitro EGFR enzyme assays and engineered cell line models revealed selectivity and antiproliferative potency of BLU-451 against a wide range of EGFR mutations in non–small cell lung cancer, including common mutations, atypical mutations, and exon 20 insertions. Particularly, BLU-451 demonstrated robust antitumor activity in EGFR exon 20 insertion cell-derived and patient-derived xenograft models and was well tolerated in animal studies. Pharmacokinetic and pharmacodynamic analyses showed that BLU-451 suppressed exon 20 insertion phosphorylated EGFR expression levels within tumor tissues but not in skin and intestinal tissues, potentially indicative of lower toxicity associated with WT EGFR. In intracranial tumor models with imaging-based analyses, BLU-451 showed CNS antitumor efficacy. Early clinical data from patients enrolled in the phase I portion of the phase I/II CONCERTO trial (NCT05241873) demonstrated the overall clinical potential of BLU-451, including its CNS antitumor activity in patients with EGFR exon 20 insertions and atypical mutations. Initial data suggest that BLU-451 is an active molecule. Further evaluation of the safety profile and pharmacokinetic properties of BLU-451 is needed.

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Cite

BibTeXRIS
BibTeX
@article{millet2026blu451,
  title = {{BLU-451, a CNS-Active, Potent, and Selective Small-Molecule Inhibitor against Uncommon EGFR Mutations}},
  author = {Yves A. Millet and Alexander I. Spira and Christina S. Baik and Min Hee Hong and Elaine Shum and Jyoti D. Patel and Danny Nguyen and Pasi A. Jänne and Zofia Piotrowska and Natasha B. Leighl and Shingo Matsumoto and Lova Sun and Tsung-Ying Yang and Tatsuya Yoshida and Monique B. Nilsson and John V. Heymach and Brion W. Murray and Jeffrey Keats and Stephanie Lee and John Hsieh and Alena Zalutskaya and Xiuning Le},
  journal = {Molecular Cancer Therapeutics},
  year = {2026},
  month = may,
  doi = {10.1158/1535-7163.mct-25-1056},
  url = {https://doi.org/10.1158/1535-7163.mct-25-1056},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - BLU-451, a CNS-Active, Potent, and Selective Small-Molecule Inhibitor against Uncommon EGFR Mutations
AU  - Yves A. Millet
AU  - Alexander I. Spira
AU  - Christina S. Baik
AU  - Min Hee Hong
AU  - Elaine Shum
AU  - Jyoti D. Patel
AU  - Danny Nguyen
AU  - Pasi A. Jänne
AU  - Zofia Piotrowska
AU  - Natasha B. Leighl
AU  - Shingo Matsumoto
AU  - Lova Sun
AU  - Tsung-Ying Yang
AU  - Tatsuya Yoshida
AU  - Monique B. Nilsson
AU  - John V. Heymach
AU  - Brion W. Murray
AU  - Jeffrey Keats
AU  - Stephanie Lee
AU  - John Hsieh
AU  - Alena Zalutskaya
AU  - Xiuning Le
PY  - 2026
DA  - 2026/05/13
JO  - Molecular Cancer Therapeutics
DO  - 10.1158/1535-7163.mct-25-1056
UR  - https://doi.org/10.1158/1535-7163.mct-25-1056
AB  - BLU-451 is a potent and selective tyrosine kinase inhibitor designed to target uncommon epidermal growth factor receptor (EGFR) mutations, spare wild-type (WT) EGFR, and be active in the central nervous system (CNS). In vitro EGFR enzyme assays and engineered cell line models revealed selectivity and antiproliferative potency of BLU-451 against a wide range of EGFR mutations in non–small cell lung cancer, including common mutations, atypical mutations, and exon 20 insertions. Particularly, BLU-451 demonstrated robust antitumor activity in EGFR exon 20 insertion cell-derived and patient-derived xenograft models and was well tolerated in animal studies. Pharmacokinetic and pharmacodynamic analyses showed that BLU-451 suppressed exon 20 insertion phosphorylated EGFR expression levels within tumor tissues but not in skin and intestinal tissues, potentially indicative of lower toxicity associated with WT EGFR. In intracranial tumor models with imaging-based analyses, BLU-451 showed CNS antitumor efficacy. Early clinical data from patients enrolled in the phase I portion of the phase I/II CONCERTO trial (NCT05241873) demonstrated the overall clinical potential of BLU-451, including its CNS antitumor activity in patients with EGFR exon 20 insertions and atypical mutations. Initial data suggest that BLU-451 is an active molecule. Further evaluation of the safety profile and pharmacokinetic properties of BLU-451 is needed.
SN  - 1535-7163
SN  - 1538-8514
ER  -