Nazartinib
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MedKoo CAT#: 206157

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

Description: Nazartinib, also known as EGF816 and NVS-816, is an orally available, irreversible, third-generation, mutant-selective epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. EGF816 covalently binds to and inhibits the activity of mutant forms of EGFR, including the T790M EGFR mutant, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGF816 preferentially inhibits mutated forms of EGFR including T790M, a secondarily acquired resistance mutation, and may have therapeutic benefits in tumors with T790M-mediated resistance when compared to other EGFR tyrosine kinase inhibitors.


Chemical Structure

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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

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10.0mg USD 150.0 Same Day
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100.0mg USD 750.0 Same Day
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Related CAS #: 1784778-10-4 (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

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

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
Soluble in DMSO 33.0 66.7

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.

Recalculate based on batch purity %
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: 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 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. Epub 2016 Jan 29. PMID: 26825170.

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  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.



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