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Purity: =99.77%
Lazertinib (formerly known as GNS-1480; YH-25448; GNS1480; YH25448; LECLAZA) is an oral, highly mutant-selective and irreversible 3rd generation EGFR TKI (Tyrosine-kinase inhibitors) approved in 2021 for the treatment of lung cancer (NSCLC). It has IC50 values of 1.7 nM, 2 nM, 5 nM, 20.6 nM, and 76 nM for Del19/T790M, L858R/T790M, Del19, L85R, and Wild type EGFR, respectively. Lazertinib is a brain-penetrant EGFR-TKI that spares wild type-EGFR in favor of activating EGFR mutations Ex19del and L858R and targeting the T790M mutation. Lazertinib was approved in January 2021 with the intention of treating patients with EGFR mutations who have locally advanced or metastatic NSCLC. EGFR single and double mutant kinase activity was selectively inhibited by lazertinib, with IC50 values of 2 nM for L858R/T790M and 76 nM for wt-EGFR. The GI50 values for H1975 cells (L858R/T790M), PC9 cells (del19), and H2073 cells (wt) in the cell proliferation assays were 6 nM, 5 nM, and 711 nM, respectively. Lazertinib exhibited a more robust inhibition of cancer cell growth in primary cancer cells from patients with EGFR mutations than osimertinib. When lazertinib was administered once daily at doses ranging from 1 to 25 mg/kg, mice implanted with H1975 cells showed dose-dependent tumor regression in both subcutaneous and intracranial lesions. There were no alterations in body weight or unusual clinical symptoms because of its high selectivity against wild type and broad safety margin. When compared to the same doses of osimertinib, lazertinib produced a more significant, complete inhibition of tumor growth and a longer overall survival at 10–25 mg/kg. Lazertinib treatment effectively inhibited pEGFR expression in tumor tissue in a dose-dependent manner, which was reflected in its in vivo effectiveness. Lazertinib had a 5.9–6.8 hour plasma half-life and a 3.0-5.1 tumor to plasma AUC0-last ratio. Additionally, lazertinib demonstrated remarkable BBB penetration, obtaining CSF concentrations that were higher than the IC50 value for pEGFR inhibition.
| Targets |
Del19/T790M (IC50 = 1.7 nM); L858R/T790M EGFR (IC50 = 2 nM); Del19 (IC50 = 5 nM); L85R (IC50 = 20.6 nM); WT EGFR (IC50 = 76 nM)
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| ln Vitro |
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| ln Vivo |
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| Enzyme Assay |
EGFR mutated lung cancer shows approximately 10-15% of non-small cell lung cancer (NSCLC). Although the best therapeutic EGFR tyrosine kinase inhibitors (TKIs) targeting mutant EGFR, such as gefitinib and erlotinib, are used in the first line treatment of patients with advanced EGFR mutated NSCLC, the acquired resistance to the drugs usually appears in 10-12 months of therapy by the occurrence of a second EGFR mutation T790M. Lazertinib (GNS-1480；YH-25448；GNS1480；YH25448；LECLAZA), a highly mutant-selective and irreversible 3rd generation EGFR TKI potently penetrating blood-brain barrier (BBB) penetration, targets both activating EGFR mutations Del19, L858R and T790M mutation while sparing wild type. In NSCLC cell lines and primary cancer cells from patients harboring EGFR mutations, YH25448 showed more potent inhibition of cancer cell growth and significantly increased tumor cell apoptosis compared to osimertinibs, which is one of 3rd generation EGFR TKIs. [1]
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| Cell Assay |
Ba/F3 cells overexpressing the designated EGFR mutant are exposed to the indicated concentrations of YH25448 or osimertinib for a duration of 6 hours. Western blot analysis is used to identify pEGFR levels.
In the cell proliferation assays, GI50 values of Lazertinib (GNS-1480；YH-25448；GNS1480；YH25448；LECLAZA) were 6 nM, 5 nM, and 711 nM for H1975 cells (L858R/T790M), PC9 cells (del19) and H2073 cells (wt), respectively. In primary cancer cells from patients harboring EGFR mutations, YH25448 showed more potent inhibition of cancer cell growth compared to osimertinib. [2] |
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| Animal Protocol |
An intracranial tumor growth model (BALB/c nude mice inoculate with H1975-luc cells)
10 and 25 mg/kg In vivo mouse model implanted with H1975 cells, YH25448 treatment at the once-daily showed a dramatic dose-dependent tumor regression in both subcutaneous and intracranial lesions with no abnormal signs such as skin keratosis shown in osimertinib-treated mice. [1] |
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| ADME/Pharmacokinetics |
Plasma half life of YH25448 was 5.9-6.8 hr and tumor to plasma AUC0-last ratio was 3.0-5.1 in tumor bearing mice. YH25448 also showed excellent penetration of the BBB, achieving CSF concentrations exceeding the IC50 value for pEGFR inhibition in the tumor-bearing mice. Taken together, these findings suggest important role for the further development of YH25448 as a novel therapeutic for the treatment of EGFR mutant-positive NSCLC patients with brain metastases.[1]
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| References | ||
| Additional Infomation |
Lazertinib is under investigation in clinical trial NCT04487080 (A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-small Cell Lung Cancer).
Lazertinib is an orally available third-generation, selective inhibitor of certain forms of the epidermal growth factor receptor (EGFR) with activating mutations, including the resistance mutation T790M, exon 19 deletions (Del19), and the L858R mutation, with potential antineoplastic activity. Upon administration, lazertinib specifically and irreversibly binds to and inhibits selective EGFR mutants, which prevents EGFR mutant-mediated signaling and leads to cell death in EGFR mutant-expressing tumor cells. Lazertinib may inhibit programmed cell death-1 ligand 1 (PD-L1) and inflammatory cytokines in specific cancer cells harboring certain EGFR mutations. Compared to some other EGFR inhibitors, lazertinib may have therapeutic benefits in tumors with T790M- or L858R-mediated drug resistance. In addition, lazertinib penetrates the blood-brain barrier (BBB). This agent shows minimal activity against wild-type EGFR (wtEGFR), and does not cause dose-limiting toxicities, which occur during the use of non-selective EGFR inhibitors and inhibit wtEGFR. EGFR, a receptor tyrosine kinase (RTK) mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. |
| Molecular Formula |
C30H34N8O3
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| Molecular Weight |
554.66
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| Exact Mass |
554.275
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| Elemental Analysis |
C, 64.96; H, 6.18; N, 20.20; O, 8.65
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| CAS # |
1903008-80-9
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| Related CAS # |
2411549-88-5 (mesylate hydrate);1903008-80-9;
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| PubChem CID |
121269225
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.647
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| LogP |
2.72
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
41
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| Complexity |
837
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O1C([H])([H])C([H])([H])N(C2=C([H])C(=C(C([H])=C2N([H])C(C([H])=C([H])[H])=O)N([H])C2=NC([H])=C([H])C(=N2)N2C([H])=C(C(C3C([H])=C([H])C([H])=C([H])C=3[H])=N2)C([H])([H])N(C([H])([H])[H])C([H])([H])[H])OC([H])([H])[H])C([H])([H])C1([H])[H]
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| InChi Key |
RRMJMHOQSALEJJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C30H34N8O3/c1-5-28(39)32-23-17-24(26(40-4)18-25(23)37-13-15-41-16-14-37)33-30-31-12-11-27(34-30)38-20-22(19-36(2)3)29(35-38)21-9-7-6-8-10-21/h5-12,17-18,20H,1,13-16,19H2,2-4H3,(H,32,39)(H,31,33,34)
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| Chemical Name |
N-[5-[[4-[4-[(dimethylamino)methyl]-3-phenylpyrazol-1-yl]pyrimidin-2-yl]amino]-4-methoxy-2-morpholin-4-ylphenyl]prop-2-enamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.9 mg/mL (1.62 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 9.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.9 mg/mL (1.62 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 9.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 0.9 mg/mL (1.62 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8029 mL | 9.0145 mL | 18.0291 mL | |
| 5 mM | 0.3606 mL | 1.8029 mL | 3.6058 mL | |
| 10 mM | 0.1803 mL | 0.9015 mL | 1.8029 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02609776 | Active Recruiting |
Drug: Lazertinib Drug: Amivantamab |
Non-Small-Cell Lung Cancer | Janssen Research & Development, LLC |
May 24, 2016 | Phase 1 |
| NCT04988295 | Active Recruiting |
Drug: Lazertinib Drug: Amivantamab |
Carcinoma, Non-Small-Cell Lung | Janssen Research & Development, LLC |
November 17, 2021 | Phase 3 |
| NCT04487080 | Active Recruiting |
Drug: Lazertinib Drug: Placebo |
Carcinoma, Non-Small-Cell Lung | Janssen Research & Development, LLC |
September 30, 2020 | Phase 3 |
| NCT05463224 | Recruiting | Drug: Lazertinib group | NSCLC | Myung-Ju Ahn | January 2, 2023 | Phase 2 |
| NCT05469022 | Recruiting | Drug: Neoadjuvant lazertinib | Non Small Cell Lung Cancer | Konkuk University Medical Center | May 19, 2022 | Phase 2 |
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