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Purity: ≥98%
Nazartinib (formerly known as EGF816, NVS-816) is a novel, covalent/irreversible, mutant-selective EGFR inhibitor with Ki and Kinact of 31 nM and 0.222 min−1 on EGFR(L858R/790M) mutant, respectively. While protecting wild-type (WT) EGFR, navartinib selectively targets EGFR-activating mutations that arise de novo and during resistance acquisition. Patients with non-small cell lung cancer who have oncogenic EGFR mutations respond to EGFR-targeted therapy initially, but as a result of acquired resistance and dose-limiting toxicities, they eventually show minimal response. In vitro, nazertinib significantly inhibits the three most prevalent EGFR mutations: L858R, Ex19del, and T790M. Three well-characterized cell lines—H3255, HCC827, and H1975—which carry the L858R, Ex19del, and L858R/T790M mutations, respectively—are used to evaluate the cellular activity of EGF816 on EGFR mutants. Patients with EGFR mutations, including T790M, are presently undergoing phase I/II clinical trials to evaluate the efficacy of napardinib.
| Targets |
EGFRL858R/T790M (Ki = 31 nM)
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| ln Vitro |
Nazartinib (EGF816) exhibits enhanced ADME and PK properties and exhibits an inhibitory effect on the mutant cell lines H1975, H3255, and HCC827, with IC50s of 4, 6, and 2 nM, respectively[1]. In H3255, HCC827, and H1975 cell lines, napardinib (EGF816) exhibits strong suppression of pEGFR levels with EC50 values of 5, 1, and 3 nM, respectively. With EC50 values of 9, 11, and 25 nM in H3255, HCC827, and H1975, respectively, nazartinib inhibits cell proliferation. On HCC827 and H1975, napartinib's OC50 (compound concentration at 50% occupancy) values are 2 and 5 nM, respectively[2].
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| ln Vivo |
Nazartinib (EGF816; 50 and 20 mg/kg or 25 mg/kg, p.o.) exhibits dose-dependent efficacy in the H1975 mouse xenograft model, with nearly complete tumor cell regression at the highest dose tested (50 mg/kg)[1]. Nazartinib (EGF816; 10 mg/kg, p.o.) in the H1975 mouse model causes tumor growth inhibition with a T/C (tumor/control volume) of 29%; tumor regressions are attained at doses of 30 and 100 mg/kg (T/C, -61% and -80%, respectively). Significant antitumor activity is demonstrated by naparsetinib (30 mg/kg, p.o.) in the H3255 xenograft model. Nazartinib selectively inhibits cell lines containing EGFR with catalytic domain mutations, as evidenced by its antiproliferative activity on 89 lung cancer cell lines[2].
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| Enzyme Assay |
In order to verify covalent modification of EGFR and site of adduction, nazartinib is incubated with the recombinant kinase domain of EGFR L858R and T790M-L858R mutants. The recombinant enzyme is incubated for one hour at room temperature with a 20-fold molar excess of the compound in 40 mM Tris, pH 8, 500 mM NaCl, 1% glycerol, and 5 mM TCEP. Addition of dithiothreitol (DTT, compound with an 80-fold excess) and cooling on ice quench the reaction. To process a third of the reaction (10 μL) for intact MS, add an equal volume of 6 M Guan HCl, 100 mM Tris, pH 8, 20 mM DTT, and 10 mM TCEP, and then incubate for 15 minutes at room temperature. With an Agilent 6520 QToF mass spectrometer that has a dual spray ion source (IS of 4500 V, fragmentor of 250 V, fas temp of 350°C, and skimmer of 75 V), intact MS analysis is carried out. The samples are heated to 60°C, injected onto a 2.1 mm x 50 mm PLRP-S column, and desalted for 2 minutes at 500 μL/min and 3% B before being eluted with a fast gradient of 3-50% B in 3 minutes (B, 0.1% formic acid). Using a mass range of 15 000–75 000 Da, the data are automatically examined in MassHunter for peak selection, integration, and spectral deconvolution.
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| Cell Assay |
In solid white 384-well plates, 500 cells are seeded per well in maintenance media. Compounds that have been serially diluted are added to cells. CellTiter-Glo is used to measure cell viability after three days. The BaF3 cell viability is assessed using the Bright-Glo Luciferase Assay System two days following compound treatment. The luminosity measurement is calibrated using cells treated with 0.1% DMSO and empty wells. Mass General Hospital generates five cell lines resistant to EGFR TKI. MGH134, MGH121, MGH141, and MGH157 are derived from patients with acquired T790M mutations who developed erlotinib resistance. Gefitinib treatment of MGH119 for an extended length of time results in the generation of MGH119-R in vitro. Nazartinib's sensitivity to these lines is examined.
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| Animal Protocol |
For efficacy studies, randomized Foxn1 nude mice with H1975 tumors are employed. The compounds are given orally via gavage at a dose volume of 10 μL/g of the animal's body weight. They are prepared in a suspension formulation of 0.5% MC and 0.5% Tween 80. Six test compounds (n = 6 in each dose group) or the vehicle (n = 6) are given orally to the animals in each group once. On day five, plasma samples are taken 30 minutes, 3 hours, 7 hours, and 24 hours after the last dosage for PK analyses. Body weight is measured every day, and [(BWcurrent-BWinitial)/(BWinitial)]×100 is the formula used to determine the percentage change in body weight. The percentage of body weight change from the day of treatment initiation is displayed for the data. Throughout the course of the five-day efficacy study, tumor sizes are measured three times. Caliper measurements are used to calculate tumor sizes. The formula for calculating tumor volumes is (length×width×width)/2.
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| References |
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| Molecular Formula |
C26H31CLN6O2
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|---|---|---|
| Molecular Weight |
495.02
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| Exact Mass |
494.22
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| Elemental Analysis |
C, 63.09; H, 6.31; Cl, 7.16; N, 16.98; O, 6.46
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| CAS # |
1508250-71-2
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| Related CAS # |
Nazartinib S-enantiomer;1508256-20-9;Nazartinib mesylate;1508250-72-3
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| Appearance |
Solid powder
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| SMILES |
CC1=NC=CC(=C1)C(=O)NC2=NC3=C(N2[C@@H]4CCCCN(C4)C(=O)/C=C/CN(C)C)C(=CC=C3)Cl
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| InChi Key |
IOMMMLWIABWRKL-WUTDNEBXSA-N
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| InChi Code |
InChI=1S/C26H31ClN6O2/c1-18-16-19(12-13-28-18)25(35)30-26-29-22-10-6-9-21(27)24(22)33(26)20-8-4-5-15-32(17-20)23(34)11-7-14-31(2)3/h6-7,9-13,16,20H,4-5,8,14-15,17H2,1-3H3,(H,29,30,35)/b11-7+/t20-/m1/s1
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| Chemical Name |
N-[7-chloro-1-[(3R)-1-[(E)-4-(dimethylamino)but-2-enoyl]azepan-3-yl]benzimidazol-2-yl]-2-methylpyridine-4-carboxamide
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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) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0201 mL | 10.1006 mL | 20.2012 mL | |
| 5 mM | 0.4040 mL | 2.0201 mL | 4.0402 mL | |
| 10 mM | 0.2020 mL | 1.0101 mL | 2.0201 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 |
| NCT03040973 | Recruiting | Drug: Capmatinib Drug: Nazartinib |
Advanced Solid Tumors Which Are cMET-dependent |
Novartis Pharmaceuticals | July 4, 2017 | Phase 2 |
| NCT03114319 | Recruiting | Drug: TNO155 in combination with EGF816 (nazartinib) Drug: TNO155 |
Advanced EGFRmutant Non Small Sell Lung Cancer (NSCLC), KRAS G12-mutant NSCLC, Esophageal SquamousCellCancer (SCC), Head/Neck SCC, Melanoma |
Novartis Pharmaceuticals | May 26, 2017 | Phase 1 |
| NCT02335944 | Terminated | Drug: Capmatinib Drug: Nazartinib |
Non Small Cell Lung Cancer | Novartis Pharmaceuticals | January 13, 2015 | Phase 1 Phase 2 |
Cellular activity of EGF816 in mutant and WT EGFR cell lines.Cancer Res.2016 Mar 15;76(6):1591-602. |
In vivo efficacy of EGF816 in EGFR-mutant–containing cell line xenograft models following 14 days (A, B, D) or 21 days (C, E, F) of once daily oral dosing.Cancer Res.2016 Mar 15;76(6):1591-602. |
EGF816 inhibits EGFR phosphorylation and downstream signaling pathways in vivo in H1975 (EGFR L858R/T790M) mouse xenograft model.Cancer Res.2016 Mar 15;76(6):1591-602. |
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