BLU-945 is a potent, highly selective, reversible and orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)[1]. EGFR plays a crucial role in cell proliferation, differentiation, survival, and migration, and its gene mutations are one of the key drivers of non-small cell lung cancer (NSCLC)[2]. BLU-945 can effectively inhibit EGFR with L858R and/or exon 19 deletion mutation, T790M mutation and C797S mutation[3]. The IC50 value of BLU-945 for EGFR L858R/C797S is 28.9nM, and for EGFR ex19del/C797S is 108.8nM[3]. BLU-945 is usually used for the research of lung cancer including non-small cell lung cancer (NSCLC)[4-7].
In vitro，BLU-945 (0-10mM; 4h) inhibited EGFR phosphorylation in cell lines harboring EGFR L858R/T790M/C797S and EGFR ex19del/T790M/C797S mutations and inhibited cell viability and growth of EGFR mutant/osimertinib-resistant cell lines[3].
In vivo, in osimertinib-resistant models of NSCLC (osimertinib second line: EGFR_L858R/C797S and third line: EGFR_ex19del/T790M/C797S and L858R/T790M/C797S), treatment of BLU-945(orally; 100mg/kg; bid; 30d) alone or combinated with osimertinib demonstrated tumor shrinkage and inhibition of the EGFR pathway[3].
References:
[1] John Emmerson Campbell, et al. Inhibitors of mutant forms of egfr. Patent WO2021133809A1.
[2] Melosky, B., Kambartel, K., Häntschel, M., Bennetts, M., Nickens, D. J., Brinkmann, J., Kayser, A., Moran, M., & Cappuzzo, F. (2022). Worldwide Prevalence of Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer: A Meta-Analysis. Molecular diagnosis & therapy, 26(1), 7–18.
[3] Lim, S. M., Schalm, S. S., Lee, E. J., Park, S., Conti, C., Millet, Y. A., Woessner, R., Zhang, Z., Tavera-Mendoza, L. E., Stevison, F., Albayya, F., Dineen, T. A., Hsieh, J., Oh, S. Y., Zalutskaya, A., Rotow, J., Goto, K., Lee, D. H., Yun, M. R., & Cho, B. C. (2024). BLU-945, a potent and selective next-generation EGFR TKI, has antitumor activity in models of osimertinib-resistant non-small-cell lung cancer. Therapeutic advances in medical oncology, 16, 17588359241280689.
[4] Eno, M. S., Brubaker, J. D., Campbell, J. E., De Savi, C., Guzi, T. J., Williams, B. D., Wilson, D., Wilson, K., Brooijmans, N., Kim, J., Özen, A., Perola, E., Hsieh, J., Brown, V., Fetalvero, K., Garner, A., Zhang, Z., Stevison, F., Woessner, R., Singh, J., … Dineen, T. A. (2022). Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer. Journal of medicinal chemistry, 65(14), 9662–9677.
[5] Kannan, K., & Mohan, S. (2025). Targeting exon mutations in NSCLC: clinical insights into LAG-3, TIM-3 pathways, and advances in fourth-generation EGFR-TKIs. Medical oncology (Northwood, London, England), 42(6), 196.
[6] Shum E, Elamin Y, Piotrowska Z, Spigel DR, Reckamp KL, Rotow J, et al.(2022). EP08.02–045 phase 1/2 study of BLU-945 in patients with common activating EGFR-mutant non-small cell lung cancer. Journal of Thoracic Oncology. 2022;17(9):S418.
[7] Elamin Y, Nagasaka M, Shum E, Bazhenova L, Camidge D, Cho B, et al. BLU-945 monotherapy and in combination with osimertinib (OSI) in previously treated patients with advanced EGFR -mutant (EGFRm) NSCLC in the phase 1/2 SYMPHONY study. J Clin Oncol. 2023;41:9011–9011.
BLU-945是一种高效、高选择性、可逆且具有口服活性的表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）[1]。EGFR在细胞增殖、分化、存活和迁移等多种生物学过程中发挥关键作用，其基因突变是非小细胞肺癌（NSCLC）的重要驱动因素之一[2]。BLU-945能够有效抑制EGFR的L858R和/或外显子19缺失突变、T790M突变以及C797S突变[3]。BLU-945对EGFR L858R/C797S的IC50值为28.9nM，对EGFR ex19del/C797S的IC50值为108.8nM[3]。BLU-945通常用于非小细胞肺癌（NSCLC）等肺癌研究[4-7]。
体外实验中，BLU-945（0-10mM；4小时）抑制了携带EGFR L858R/T790M/C797S和EGFR ex19del/T790M/C797S突变的细胞系中EGFR的磷酸化，并抑制了EGFR突变/奥希替尼耐药细胞系的细胞活性和生长[3]。
体内实验中，在奥希替尼耐药的NSCLC模型中（奥希替尼二线治疗：EGFR L858R/C797S；奥希替尼三线治疗：EGFR ex19del/T790M/C797S和L858R/T790M/C797S），无论是单药治疗还是与奥希替尼联合使用，BLU-945（口服；100 mg/kg；每日两次；30天）均显示出肿瘤缩小和EGFR信号通路的抑制[3]。