Lazertinib
(Synonyms: YH25448; GNS-1480) 目录号 : GC19218
Lazertinib是一种有效的、高度突变选择性的、能穿透血脑屏障的、口服的、不可逆的第三代EGFR酪氨酸激酶抑制剂。
Cas No.:1903008-80-9
Sample solution is provided at 25 µL, 10mM.
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Lazertinib is a potent, highly mutant-selective, blood-brain barrier permeable, orally available and irreversible third-generation EGFR tyrosine kinase inhibitor[1]. Lazertinib selectively and potently inhibits the T790M, L858R, and Del19 mutations of EGFR, while its inhibitory activity against wild - type EGFR is relatively low[2]. Lazertinib inhibits EGFR phosphorylation and prevents downstream signaling of the mitogen-activated protein kinase (MAPK) and PI3K/Akt/mTOR (PAM) pathways, thereby halting cancer cell growth and proliferation, and is commonly used in the research of non-small cell lung cancer (NSCLC)[3-4].
In vitro, treatment of Ba/F3 cells harboring Del19, L858R, Del19/T790M, and L858R/T790M mutations with Lazertinib(5, 10, 100nM; 72h) showed a dose-dependent inhibition of EGFR phosphorylation and reduced cell viability with mean IC50 values in the low nanomolar range (3.3-5.7nM)[5]. Treatment of the non-small cell lung cancer (NSCLC) cell line H1975 with Lazertinib(0-100nM; 72h) demonstrated significant anti-proliferative activity with an IC50 value of less than 1nM, while in the glioblastoma (GBM) cell line U87-EGFRvIII, the IC50 value of Lazertinib was greater than 100nM[6].
In vivo, combination treatment of Lazertinib (10mg/kg; p.o.; 29 days) and amivantamab in uncommon EGFR-mutant NSCLC mice demonstrates potent antitumor activity by overcoming resistance to EGFR-TKIs, enhancing amivantamab's on-target expression, and upregulating of EGFR/MET expression[7].
References:
[1] Cho BC, Felip E, Hayashi H, et al. MARIPOSA: phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer. Future Oncol. 2022;18(6):639-647.
[2] Shah D, Shah D, Ndandji S, Kar S. Lazertinib: a novel EGFR-TKI therapy for non-small cell lung cancer. Expert Opin Drug Metab Toxicol. 2025;21(7):789-800.
[3] Hong MH, Choi YJ, Ahn HK, et al. Lazertinib in EGFR-Variant Non-Small Cell Lung Cancer With CNS Failure to Prior EGFR Tyrosine Kinase Inhibitors: A Nonrandomized Controlled Trial. JAMA Oncol. 2024;10(10):1342-1351.
[4] Cho BC, Lu S, Felip E, et al. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498.
[5] Yun J, Hong MH, Kim SY, et al. YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non-Small Cell Lung Cancer. Clin Cancer Res. 2019;25(8):2575-2587.
[6] Yang H, Yan R, Jiang Y, et al. Design, synthesis and biological evaluation of 2-amino-4-(1,2,4-triazol)pyridine derivatives as potent EGFR inhibitors to overcome TKI-resistance. Eur J Med Chem. 2020;187:111966.
[7] Oh SY, Park S, Lee S, et al. The potential of lazertinib and amivantamab combination therapy as a treatment strategy for uncommon EGFR-mutated NSCLC. Cell Rep Med. 2025;6(2):101929.
Lazertinib是一种有效的、高度突变选择性的、能穿透血脑屏障的、口服的、不可逆的第三代EGFR酪氨酸激酶抑制剂[1]。Lazertinib选择性地强效抑制T790M、L858R和Del19突变的EGFR，而对野生型EGFR的抑制活性相对较低[2]。Lazertinib抑制EGFR磷酸化，并阻止丝裂原活化蛋白激酶（MAPK）和PI3K/Akt/mTOR（PAM）通路的下游信号传导，从而抑制癌细胞的生长和增殖，常用于非小细胞肺癌（NSCLC）的研究[3-4]。
在体外，Lazertinib（5，10，100nM；72小时）处理携带Del19、L858R、Del19/T790M和L858R/T790M突变的Ba/F3细胞，显示出剂量依赖性的EGFR磷酸化抑制，并降低细胞活力，平均IC50值在低纳摩尔范围（3.3-5.7nM）内[5]。用Lazertinib（0-100nM；72小时）处理非小细胞肺癌（NSCLC）细胞系H1975，显示出显著的抗增殖活性，IC50值小于1nM；而在胶质母细胞瘤（GBM）细胞系U87-EGFRvIII中，Lazertinib的IC50值大于100nM[6]。
在体内，Lazertinib（10mg/kg；口服；29天）与amivantamab联合治疗不常见EGFR突变NSCLC小鼠可通过克服对EGFR-TKIs的耐药性，增强amivantamab的靶向表达，并上调EGFR/MET表达，表现出强大的抗肿瘤活性[7]。
| Kinase experiment [1]: | |
Preparation Method | Cell-free kinase assays were conducted using Lance Ultra timeresolved fluorescence resonance energy transfer (TR-FRET) technology from Perkin-Elmer. Briefly, each EGFR enzyme WT, single mutant (Del19, L858R, and T790M), double mutant (L858R/ T790M, Del19/T790M), Her2 or Her4, serial diluted Lazertinib(0.01-10μM), substrate of ULight-poly-GT peptide and variable amounts of ATP (8.5–1,088mmol/L) were mixed in kinase assay buffer (50mM HEPES pH7.5, 10mM MgCl2, 1mM EGTA, 2mM DTT, and 0.01% Tween-20) and were added to a 96-well plate. Kinase reactions were incubated at room temperature for 1 hour and then stopped by the addition of 5μL of 10mM EDTA. The specific Europium-labeled-anti-phosphopeptide antibody diluted in LANCE detection buffer was then added to a final concentration of 2nM. After 30-minute incubation, the LANCE signal was measured on an EnVision Multilabel Reader. Excitation wavelength was set at 320nm and emission monitored at 615nm (donor) and 665nm (acceptor). The IC50 values were determined using GraphPad Prism. |
Reaction Conditions | 0.01-10μM; 1h |
Applications | Lazertinib at a concentration of 1μM inhibited kinase activities of EGFRs, with percentages of inhibition >85%. |
| Cell experiment [1]: | |
Cell lines | NSCLC cells |
Preparation Method | Human NSCLC cells with an EGFR mutation were maintained in RPMI 1640 medium supplemented with 10% FBS and 1% solution of antibiotics in a humidified incubator with 5% CO2. Cells were seeded onto 96-well plates in 100μL. After treatment with Lazertinib(5, 10, 100nM) for 72 hours, cell viability was measured by quantifying the total amount of ATP using the CellTiter-Glo 2.0 Assay Kit per the manufacturer's instruction. Dose–response curves were fitted to the data using the GraphPad Prism. |
Reaction Conditions | 5, 10, 100nM; 72h |
Applications | Lazertinib reduced the viability of cells harboring mutant EGFRs. |
| Animal experiment [2]: | |
Animal models | EGFR-mutant NSCLC mice models |
Preparation Method | To generate YU-1092, YUO-139 Patient-derived cell (PDC) and Patient-derived organoids (PDO）-derived tumor xenograft models, cells (5×106 in 100μL) were implanted subcutaneously into the flanks of 6-week-old female nu/nu mice. Once the tumor size reached 150-200mm2 , the mice were randomly allocated and assigned to the respective treatment groups as follows: vehicle, Lazertinib (10mg/kg; oral daily), amivantamab (10mg/kg, subcutaneous (SC), twice per week), and combination with either Lazertinib or amivantamab. Within 29 days after administration，the tumor size was measured with an electronic caliper. Body weight of tumor bearing mice was monitored every other of the experiment. |
Dosage form | 10mg/kg/day for 29 days; p.o. |
Applications | Combination treatment of Lazertinib and amivantamab demonstrates potent antitumor activity. |
References: | |
| Cas No. | 1903008-80-9 | SDF | |
| 别名 | YH25448; GNS-1480 | ||
| Canonical SMILES | C=CC(NC1=CC(NC2=NC=CC(N3N=C(C4=CC=CC=C4)C(CN(C)C)=C3)=N2)=C(OC)C=C1N5CCOCC5)=O | ||
| 分子式 | C30H34N8O3 | 分子量 | 554.64 |
| 溶解度 | DMSO : 9 mg/mL (16.23 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.803 mL | 9.0149 mL | 18.0297 mL |
| 5 mM | 0.3606 mL | 1.803 mL | 3.6059 mL |
| 10 mM | 0.1803 mL | 0.9015 mL | 1.803 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
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- Purity: >98.00%
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