Neratinib (HKI-272)

Neratinib (HKI-272) is a highly selective HER2 and EGFR inhibitor with IC50 of 59 nM and 92 nM in cell-free assays; weakly inhibits KDR and Src, no significant inhibition to Akt, CDK1/2/4, IKK-2, MK-2, PDK1, c-Raf and c-Met. Phase 3.

Price Stock Quantity  
In DMSO USD 360 In stock
USD 150 In stock
USD 470 In stock
USD 970 In stock
Bulk Inquiry

Massive Discount Available

Free Overnight Delivery on all orders over $ 500.

Neratinib (HKI-272) Chemical Structure

Neratinib (HKI-272) Chemical Structure
Molecular Weight: 557.04

Validation & Quality Control

Customer Product Validation(3)

Quality Control & MSDS

Related Compound Libraries

HER2 Inhibitors with Unique Features

Product Information

  • Compare HER2 Inhibitors
    Compare HER2 Products
  • Research Area
  • Inhibition Profile

Product Description

Biological Activity

Description Neratinib (HKI-272) is a highly selective HER2 and EGFR inhibitor with IC50 of 59 nM and 92 nM in cell-free assays; weakly inhibits KDR and Src, no significant inhibition to Akt, CDK1/2/4, IKK-2, MK-2, PDK1, c-Raf and c-Met. Phase 3.
Targets HER2 [1]
(Cell-free assay)
EGFR [1]
(Cell-free assay)
KDR [1]
(Cell-free assay)
Src [1]
(Cell-free assay)

 View  More

IC50 59 nM 92 nM 800 nM 1.4 μM
In vitro Neratinib weakly inhibits tyrosine kinases KDR and Src with IC50 of 0.8 μM and 1.4 μM, respectively, being 14- and 24-fold less active compared with HER2. Neratinib displays no activity against other serine-threonine kinases such as Akt, cyclin D1/cdk4, cyclin E/cdk2, cyclin B1/cdk1, IKK-2, MK-2, PDK1, c-Raf, and Tpl-2, as well as the tyrosine kinase c-Met. Neratinib selectively inhibits the proliferation of 3T3 cells transfected with the HER2 (3T3/neu), as well as two other HER-2-overexpressing SK-Br-3 and BT474 cells with IC50 values of 2-3 nM, displaying >230-fold potency compared with non-transfected 3T3 cells as well as MDA-MB-435 and SW620 which are EGFR- and HER2-negative. Neratinib also inhibits the proliferation of EGFR-dependent A431 cells with an IC50 of 81 nM. Neratinib reduces HER2 receptor autophosphorylation in BT474 cells with an IC50 of 5 nM, and EGF-dependent phosphorylation of EGFR in A431 cells with IC50 of 3 nM. Blocking of HER-2 by Neratinib results in inhibition of downstream MAPK and Akt pathways with IC50 of 2 nM, more potently than Trastuzumab. Neratinib inhibits the cyclin D1 expression and the phosphorylation of the Rb-susceptibility gene production in BT474 cells with IC50 of 9 nM, leading to G1-S arrest and ultimately decreased cell proliferation. [1]
In vivo Oral administration of Neratinib significantly inhibits the growth of 3T3/neu xenografts, with inhibition of 34%, 53%, 98%, and 98% at dose of 10, 20, 40, and 80 mg/kg/day, respectively. Consistent with the inhibition of HER-2 phosphorylation by 84% within 1 hour of administration at 40 mg/kg/day, Neratinib inhibits the growth of BT474 xenografts by 70-82%, 67%, and 93% at dose of 5, 10, and 40 mg/kg/day, respectively. Neratinib is also effective against SK-OV-3 xenografts with inhibition of 31% and 85% at 5 and 60 mg/kg/day, respectively. Neratinib is less potent against EGFR-dependent A431 xenografts than HER-2-dependent tumors, with 32% and 44% inhibition at 5 and 20 mg/kg/day, respectively. Neratinib displays little activity against MCF-7 and MX-1 xenografts expressing low levels of HER-2 and EGFR, with only 28% inhibition at 80 mg/kg/day, suggesting that Neratinib has selective activity for cells expressing HER-2 or EGFR. [1]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Cell-free autophosphorylation assay using time-resolved fluorometry Neratinib is prepared as 10 mg/mL stocks in DMSO and diluted in 25 mM HEPES (pH 7.5; 0.002 ng/mL-20 μg/mL). Purified recombinant COOH-terminal fragments of HER2 (amino acids 676-1255) or epidermal growth factor receptor (EGFR) (amino acids 645-1186) [diluted in 100 mM HEPES (pH 7.5) and 50% glycerol] is incubated with increasing concentrations of Neratinib in 4 mM HEPES (pH 7.5), 0.4 mM MnCl2, 20 μM sodium vanadate, and 0.2 mM DTT for 15 minutes at room temperature in 96-well ELISA plates. The kinase reaction is initiated by the addition of 40 μM ATP and 20 mM MgCl2 and allowed to proceed for 1 hour at room temperature. Plates are washed, and phosphorylation is detected using Europium-labeled anti-phospho-tyrosine antibodies (15 ng/well). After washing and enhancement steps, signal is detected using a Victor2 fluorescence reader (excitation wavelength 340 nm, emission wavelength 615 nm). The concentration of Neratinib that inhibits receptor phosphorylation by 50% (IC50) is calculated from inhibition curves.

Cell Assay: [1]

Cell lines 3T3, 3T3/neu, A431, BT474, SK-Br-3, MDA-MB-435, and SW480
Concentrations Dissolved in DMSO, final concentrations 0.5 ng/mL-5 μg/mL
Incubation Time 2 or 6 days
Method Cells are exposed to various concentrations of Neratinib for 2, or 6 days. Cell proliferation is determined using sulforhodamine B, a protein binding dye. Briefly, cells are fixed with 10% trichloroacetic acid and washed extensively with water. Cells are then stained with 0.1% sulforhodamine B and washed in 5% acetic acid. Protein-associated dye is solubilized in 10 mM Tris, and absorbance is measured at 450 nM. The concentration of Neratinib that inhibits cell proliferation by 50% (IC50) is determined from inhibition curves.

Animal Study: [1]

Animal Models Female athymic (nude) mice implanted s.c. with 3T3/neu, BT474, MCF-7, or SK-OV-3 cells
Formulation Formulated in 0.5% methocellulose-0.4% polysorbate-80 (Tween 80)
Dosages ~80 mg/kg/day
Administration Gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Rabindran SK, et al. Cancer Res, 2004, 64(11), 3958-3965.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-06-27)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02400476 Recruiting Early Stage HER2+ Breast Cancer Puma Biotechnology, Inc. February 2015 Phase 2
NCT02236000 Recruiting Breast Cancer NSABP Foundation Inc|Puma Biotechnology, Inc. August 2014 Phase 1|Phase 2
NCT02334501 Completed Healthy Puma Biotechnology, Inc. August 2014 Phase 1
NCT01960023 Recruiting Colorectal Cancer NSABP Foundation Inc October 2013 Phase 1|Phase 2
NCT01953926 Recruiting Solid Tumors Puma Biotechnology, Inc. September 2013 Phase 2

view more

Chemical Information

Download Neratinib (HKI-272) SDF
Molecular Weight (MW) 557.04
Formula

C30H29ClN6O3

CAS No. 698387-09-6
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 2 mg/mL (3.59 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 5 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide

Customer Product Validation (3)


Click to enlarge
Rating
Source Cancer Discov 2013 3, 224-37. Neratinib (HKI-272) purchased from Selleck
Method Colony assays
Cell Lines MCF10A cells
Concentrations 0.5 μmol/L
Incubation Time a week
Results Treatment with lapatinib and neratinib inhibited the growth of these invasive colonies.

Click to enlarge
Rating
Source Cancer Discov 2012 2, 458-471. Neratinib (HKI-272) purchased from Selleck
Method Western Blot
Cell Lines SKMG3
Concentrations 200-1800 nM
Incubation Time 3 day
Results Immunoblots of whole-cell lysates from SKMG3 cells treated with either inhibitor showed that CI-1033 inhibited EGFR phosphorylation less effectively than HKI-272 (Fig. C).

Click to enlarge
Rating
Source Cancer Discov 2012 2, 458-471. Neratinib (HKI-272) purchased from Selleck
Method Cell Death Assay
Cell Lines Glioma & Lung cancer cell lines
Concentrations 125-2000 nM
Incubation Time 5 day
Results HKI-272 induced cell death in SF268 and SKMG3 cells but not in EGFR wild-type GBM (SF295, 8-MG-BA), lung cancer cells (H460), or human astrocytes (NHA; Fig. A).

Product Use Citation (10)

Tech Support & FAQs

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.

Tel: +1-832-582-8158 Ext:3

If you have any other enquiries, please leave a message.

* Indicates a Required Field

Related HER2 Products

  • Erlotinib

    Erlotinib is an EGFR inhibitor with IC50 of 2 nM, >1000-fold more sensitive for EGFR than human c-Src or v-Abl.

  • BLZ945

    BLZ945 is an orally active, potent and selective CSF-1R inhibitor with IC50 of 1 nM, >1000-fold selective against its closest receptor tyrosine kinase homologs.

  • PF-06463922

    PF-06463922 is a potent, dual ALK/ROS1 inhibitor with Ki of <0.02 nM, <0.07 nM, and 0.7 nM for ROS1, ALK (WT), and ALK (L1196M), respectively. Phase 1.

  • Lapatinib (GW-572016) Ditosylate

    Lapatinib (GW-572016) Ditosylate is a potent EGFR and ErbB2 inhibitor with IC50 of 10.8 and 9.2 nM in cell-free assays, respectively.

  • AC480 (BMS-599626)

    AC480 (BMS-599626) is a selective and efficacious inhibitor of HER1 and HER2 with IC50 of 20 nM and 30 nM, ~8-fold less potent to HER4, >100-fold to VEGFR2, c-Kit, Lck, MET etc. Phase 1.

  • CP-724714

    CP-724714 is a potent, selective inhibitor of HER2/ErbB2 with IC50 of 10 nM, >640-fold selectivity against EGFR, InsR, IRG-1R, PDGFR, VEGFR2, Abl, Src, c-Met etc in cell-free assays. Phase 2.

  • AZD8931 (Sapitinib)

    AZD8931 (Sapitinib) is a reversible, ATP competitive inhibitor of EGFR, ErbB2 and ErbB3 with IC50 of 4 nM, 3 nM and 4 nM in cell-free assays, more potent than Gefitinib or Lapatinib against NSCLC cell, 100-fold more selective for the ErbB family than MNK1 and Flt. Phase 2.

  • Mubritinib (TAK 165)

    Mubritinib (TAK-165) is a potent inhibitor of HER2/ErbB2 with IC50 of 6 nM in BT-474 cell; no activity to EGFR, FGFR, PDGFR, JAK1, Src and Blk in BT-474 cell line. Phase 1.

  • Tyrphostin AG 879

    Tyrphostin AG 879 potently inhibits HER2/ErbB2 with IC50 of 1 μM, 100- and 500-fold higher selective to ErbB2 than PDGFR and EGFR.

  • Gefitinib (ZD1839)

    Gefitinib (ZD-1839) is an EGFR inhibitor for Tyr1173, Tyr992, Tyr1173 and Tyr992 in the NR6wtEGFR and NR6W cells with IC50 of 37 nM, 37nM, 26 nM and 57 nM, respectively.

    Features:A potent EGFR tyrosine kinase inhibitor.

Recently Viewed Items

Tags: buy Neratinib (HKI-272) | Neratinib (HKI-272) supplier | purchase Neratinib (HKI-272) | Neratinib (HKI-272) cost | Neratinib (HKI-272) manufacturer | order Neratinib (HKI-272) | Neratinib (HKI-272) distributor
×
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description
Contact Us