Nazartinib | EGF816 | CAS#1508250-71-2 (free base) | EGFR inhibitor

MedKoo Cat#: 206157 | Name: Nazartinib

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Nazartinib (EGF816, NVS-816) is a third-generation, orally bioavailable epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) developed by Novartis, designed to selectively target mutant forms of EGFR including the T790M resistance mutation commonly found in non-small cell lung cancer (NSCLC). In preclinical studies, Nazartinib demonstrated potent inhibition of EGFR phosphorylation in cell lines harboring activating EGFR mutations (e.g., L858R, exon 19 deletions) and T790M mutations, with IC₅₀ values in the low nanomolar range (e.g., ~2–5 nM for mutant EGFR in vitro), while sparing wild-type EGFR (IC₅₀ ~500 nM or higher), suggesting a favorable therapeutic index. In xenograft models, Nazartinib significantly reduced tumor growth in EGFR T790M-positive NSCLC models.

Chemical Structure

Nazartinib

CAS#1508250-71-2 (free base)

Theoretical Analysis

MedKoo Cat#: 206157

Name: Nazartinib

CAS#: 1508250-71-2 (free base)

Chemical Formula: C26H31ClN6O2

Exact Mass: 494.2197

Molecular Weight: 495.02

Elemental Analysis: C, 63.09; H, 6.31; Cl, 7.16; N, 16.98; O, 6.46

Price and Availability

Size	Price	Availability
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship

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Related CAS #

1784778-10-4 (mesylate hydrate) 1508250-72-3 (mesylate) 1508250-71-2 (free base)

Synonym

EGF816; EGF-816; EGF 816; NVS-816; NVS 816; NVS816; Nazartinib.

IUPAC/Chemical Name

(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide

InChi Key

IOMMMLWIABWRKL-WUTDNEBXSA-N

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

SMILES Code

O=C(NC1=NC2=CC=CC(Cl)=C2N1[C@H]3CN(C(/C=C/CN(C)C)=O)CCCC3)C4=CC=NC(C)=C4

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A8T03K12

QC Data

View QC data: current batch, Lot#A8T03K12

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Nazartinib (EGF816) is a covalent mutant-selective EGFR inhibitor, with Ki and Kinact of 31 nM and 0.222 min−1 on EGFR(L858R/790M) mutant, respectively.

In vitro activity:

The cellular activity of EGF816 on EGFR mutants were assessed using three well-characterized cell lines, H3255, HCC827, and H1975, which harbor the L858R, Ex19del, and L858R/T790M mutations, respectively. After incubation with cells for 3 hours, EGF816 showed potent inhibition of pEGFR levels in H3255, HCC827, and H1975 with EC50 values of 5, 1, and 3 nmol/L, respectively (Table 1; Fig. 1A). EGF816 was further evaluated for its ability to inhibit cell proliferation, where it produced EC50 values of 9, 11, and 25 nmol/L in H3255, HCC827, and H1975, respectively (Table 1; Fig. 1B). In contrast, erlotinib showed weak inhibitory effect on H1975 as expected, with EC50 values of 1,400 and 7,400 nmol/L in target modulation and proliferation assays, respectively (Fig. 1A and B). In addition, EGF816 was also tested in a panel of cell line models established directly from erlotinibresistant patient biopsy samples that had acquired a T790M-resistant mutation. These cell lines were resistant to gefitinib; however, they were all sensitive to EGF816 treatment (Fig. 1C; Supplementary Table S1). As expected, EGF816 was also effective on the erlotinib-sensitive patient-derived cell line MGH119 (EGFR Ex19del mutation), but not on the WT EGFR-containing patient-derived cell lines MGH025 and NH11. Taken together, these data demonstrate that EGF816 is a potent inhibitor of cells driven by mutant EGFR. Cancer Res. 2016 Mar 15;76(6):1591-602. https://cancerres.aacrjournals.org/content/76/6/1591.long

In vivo activity:

To confirm the in vivo efficacy of EGF816 was due to its ability to effectively suppress EGFR signaling, a single-dose experiment was conducted in both H1975 and HCC827 mouse xenograft models to examine the kinetics of target inhibition by EGF816 with respect to plasma exposure. In both models, there was a dose-dependent increase in both the extent and duration of pEGFR inhibition (Fig. 3A, Supplementary Fig. S3A). In the H1975 model, at 3 and 10 mg/kg, the pEGFR levels were inhibited partially within the 24hour period. At 30 mg/kg, the dose that gave significant tumor regression in the 14-day efficacy study (Fig. 2A), inhibition of pEGFR was observed as early as 1-hour postdose and was maintained through 24 hours with >80% inhibition. Levels of pEGFR returned to baseline at 48-hour postdose (Fig. 3A). In addition, downstream biomarkers such as pAKT and pERK were also inhibited as early as 1-hour postdose and maintained for ≥7-hour postdose, and returned to baseline levels at 16- to 24-hour postdose (Fig. 3B). In the HCC827 model, at 1 mg/kg, the pEGFR level was inhibited partially within the 24-hour period, but at 3 and 10 mg/kg, the doses that gave significant tumor regression in the 14-day efficacy study (Fig. 2C), pEGFR levels were inhibited for >80% within the 24-hour period (Supplementary Fig. S3A). Inhibition of pEGFR and downstream biomarkers such as pAKT and pERK was observed as early as 1-hour postdose and was maintained through 24-hour post-single oral dose of EGF816 at 10 mg/kg (Supplementary Fig. S3B). Together, these data suggest that sustained high level inhibition of pEGFR is required for good antitumor efficacy in mouse xenograft models. Cancer Res. 2016 Mar 15;76(6):1591-602. https://cancerres.aacrjournals.org/content/76/6/1591.long

	Solvent	mg/mL	mM
Solubility
	Soluble in DMSO	33.0	66.70

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 495.02 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Jia Y, Juarez J, Li J, Manuia M, Niederst MJ, Tompkins C, Timple N, Vaillancourt MT, Pferdekamper AC, Lockerman EL, Li C, Anderson J, Costa C, Liao D, Murphy E, DiDonato M, Bursulaya B, Lelais G, Barretina J, McNeill M, Epple R, Marsilje TH, Pathan N, Engelman JA, Michellys PY, McNamara P, Harris J, Bender S, Kasibhatla S. EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor. Cancer Res. 2016 Mar 15;76(6):1591-602. doi: 10.1158/0008-5472.CAN-15-2581. Epub 2016 Jan 29. PMID: 26825170.

In vitro protocol:

In vivo protocol:

1: Jia Y, Juarez J, Li J, Manuia M, Niederst MJ, Tompkins C, Timple N, Vaillancourt MT, Pferdekamper AC, Lockerman EL, Li C, Anderson J, Costa C, Liao D, Murphy E, DiDonato M, Bursulaya B, Lelais G, Barretina J, McNeill M, Epple R, Marsilje TH, Pathan N, Engelman JA, Michellys PY, McNamara P, Harris J, Bender S, Kasibhatla S. EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor. Cancer Res. 2016 Mar 15;76(6):1591-602. doi: 10.1158/0008-5472.CAN-15-2581. PubMed PMID: 26825170. 2: Lelais G, Epple R, Marsilje TH, Long YO, McNeill M, Chen B, Lu W, Anumolu J, Badiger S, Bursulaya B, DiDonato M, Fong R, Juarez J, Li J, Manuia M, Mason DE, Gordon P, Groessl T, Johnson K, Jia Y, Kasibhatla S, Li C, Isbell J, Spraggon G, Bender S, Michellys PY. Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imid azol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers. J Med Chem. 2016 Jul 28;59(14):6671-89. doi: 10.1021/acs.jmedchem.5b01985. PubMed PMID: 27433829. 3: Liao BC, Lin CC, Lee JH, Yang JC. Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors. J Biomed Sci. 2016 Dec 3;23(1):86. Review. PubMed PMID: 27912760; PubMed Central PMCID: PMC5135794. 4: Wang S, Cang S, Liu D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol. 2016 Apr 12;9:34. doi: 10.1186/s13045-016-0268-z. Review. PubMed PMID: 27071706; PubMed Central PMCID: PMC4830020. 5: Sun JM, Park K. Can we define the optimal sequence of epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of epidermal growth factor receptor-mutant nonsmall cell lung cancer? Curr Opin Oncol. 2017 Mar;29(2):89-96. doi: 10.1097/CCO.0000000000000350. PubMed PMID: 28085680. 6: Kobayashi Y, Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy. Cancer Sci. 2016 Sep;107(9):1179-86. doi: 10.1111/cas.12996. Review. PubMed PMID: 27323238; PubMed Central PMCID: PMC5021039. 7: Ou SH, Soo RA. Dacomitinib in lung cancer: a "lost generation" EGFR tyrosine-kinase inhibitor from a bygone era? Drug Des Devel Ther. 2015 Oct 15;9:5641-53. doi: 10.2147/DDDT.S52787. Review. PubMed PMID: 26508839; PubMed Central PMCID: PMC4610796.