Nazartinib (EGF816)

Catalog No.S7824 Synonyms: NVS-816

For research use only.

Nazartinib (EGF816, NVS-816) is a covalent, irreversible, mutant-selective EGFR inhibitor that has nanomolar inhibitory potency against activating mt (L858R, ex19del) and T790M mt, with up to 60-fold selectivity over wild type (wt) EGFR in vitro.

Nazartinib (EGF816) Chemical Structure

CAS No. 1508250-71-2

Selleck's Nazartinib (EGF816) has been cited by 5 Publications

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Biological Activity

Description Nazartinib (EGF816, NVS-816) is a covalent, irreversible, mutant-selective EGFR inhibitor that has nanomolar inhibitory potency against activating mt (L858R, ex19del) and T790M mt, with up to 60-fold selectivity over wild type (wt) EGFR in vitro.
Targets
mutant EGFR [2]
0.031 μM(Ki)
In vitro

EGF816 is a novel, covalent, mutant-selective EGFR inhibitor with nearly equipotent activity on both oncogenic (L858R and ex19del) and T790M-resistant mutations and good selectivity over WT EGFR[1]. EGF816 potently inhibits the most common EGFR mutations L858R, Ex19del, and T790M in vitro. The cellular activity of EGF816 on EGFR mutants are 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 shows potent inhibition of pEGFR levels in H3255, HCC827, and H1975 with EC50 values of 5, 1, and 3 nmol/L, respectively. Cellular-based assays shows that EGF816 is selective toward mutant over WT EGFR[2].

In vivo EGF816 is well tolerated and possesses favorable physicochemical properties and good oral bioavailability in mice. It shows moderate volume of distribution and low to moderate clearance in rodents (30% and 35% of rat and mouse liver blood flow, respectively). In the dog, EGF816 shows high clearance and high volume of distribution[1]. EGF816 also demonstrates antitumor activity in an exon 20 insertion mutant model. At levels above efficacious doses, EGF816 treatment leads to minimal inhibition of WT EGFR and is well tolerated. In single-dose studies, EGF816 provides sustained inhibition of EGFR phosphorylation, consistent with its ability for irreversible binding. EGF816 has a longer half-life in human than mouse and is currently being evaluated in phase I/II clinical trials in patients harboring EGFR mutations, including T790M[2].

Protocol (from reference)

Cell Research:[2]
  • Cell lines: H1975, H3255, HCC827, A431, and HaCaT cells
  • Concentrations: --
  • Incubation Time: 3 h
  • Method: H1975, H3255, HCC827, A431, and HaCaT cells are maintained in RPMI media supplemented with antibiotics and 10% FBS, maintained in a 37°C, 5% CO2 humidified incubator. After an overnight incubation in 384-well plates, serial diluted compounds are transferred to cells and incubated for 3 hours. HaCaT cells are stimulated with 10 ng/mL EGF (50 ng/mL EGF for A431) for 5 minutes. Cells are lysed in 1% Triton X-100 buffer containing protease and phosphatase inhibitors. Lysates are analyzed by sandwich ELISA utilizing goat anti-EGFR capture antibody, anti-phospho-EGFR(Y1173), and anti-rabbit HRP. Signal is measured by chemiluminescent detection.
Animal Research:[1]
  • Animal Models: balb/c mice and male Wistar rats
  • Dosages: 50 mg/kg
  • Administration: oral administration

Solubility (25°C)

In vitro

Chemical Information

Molecular Weight 495.02
Formula

C26H31ClN6O2

CAS No. 1508250-71-2
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC1=NC=CC(=C1)C(=O)NC2=NC3=C(N2C4CCCCN(C4)C(=O)C=CCN(C)C)C(=CC=C3)Cl

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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03529084 Withdrawn Drug: EFG816|Drug: erlotinib or gefitinib Carcinoma Non-small Cell Lung Novartis Pharmaceuticals|Novartis July 24 2018 Phase 3
NCT03516214 Recruiting Drug: EGF816|Drug: Trametinib Bronchial Neoplasms University of Cologne April 25 2018 Phase 1
NCT03292133 Active not recruiting Drug: EGF816|Drug: Gefitinib Lung Cancer Massachusetts General Hospital|Novartis October 31 2017 Phase 2
NCT02323126 Terminated Drug: EGF816|Drug: INC280|Drug: Nivolumab Non Small Cell Lung Cancer Novartis Pharmaceuticals|Novartis February 9 2015 Phase 2
NCT02335944 Terminated Drug: Capmatinib|Drug: Nazartinib Non Small Cell Lung Cancer Novartis Pharmaceuticals|Novartis January 13 2015 Phase 1|Phase 2

(data from https://clinicaltrials.gov, updated on 2022-08-01)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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