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Fig. 1 · Structure
Cat. No.
A10638
CAS No.
698387-09-6
Formula
C30H29ClN6O3
Mol. Weight
557

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Neratinib (HKI-272)

HER2 inhibitor

Neratinib (HKI-272) is a tyrosine kinase inhibitor.

In Stock

Publications for Neratinib

3 publications citing this product

  1. Majid Momeny, .et al. , EMBO Mol Med, 2024, Jun 17 PMID: 38886591
  2. Hamzehlou S, .et al. , Eur J Pharmacol, 2019, Nov 15;863:172705 PMID: 31574259
  3. Li Li, .et al. , Leukemia Res, 2019, 78:12-20 PMID: 30660961
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Biological Activity

Bioactivity / Mechanism

In HER2-amplified H2170 and Calu-3 cells and HER2-mutant H1781 cells, neratinib suppressed HER2/EGFR phosphorylation and downstream AKT/MAPK phosphorylation after 6 h. These cellular results support inhibition of HER-family signaling; they do not by themselves establish irreversible binding kinetics. [1]

Literature-reported observations and conditions; not Adooq-tested protocols or general treatment recommendations.

Target & Activity

Target Activity Value
HER2 IC50 59nM
EGFR IC50 92nM
KDR IC50 800nM
Src IC50 1.4μM
PDK-1 IC50 >5μM
IKK2 IC50 >9μM
CDK2/CyclinE IC50 >18μM
CDK1/CyclinB1 IC50 >18μM
C-Raf/MEK1 IC50 >18μM
Tpl-2 IC50 >18μM
Akt IC50 >20μM
c-Met IC50 >35μM
MK2 IC50 >45μM
CDK4/CyclinD1 IC50 >50μM

14 targets · Scroll to view more

Cellular Effect

Cell Line Activity Value Description Reference
BaF3 GI50 1.9 μM Growth inhibition of mouse BAF3 cells after 72 hrs by CellTiter-Glo assay [PMID: 28282122]
BT-474 IC50 2.06 nM Antiproliferative activity against human BT-474 cells assessed as inhibition of cell growth incubated for 72 hrs by Celltiter-Glo assay [PMID: 35319895]
COLO-678 IC50 694.11 nM Antiproliferative activity against human COLO-678 cells assessed as cell growth inhibition incubated for 72 hrs by Celltiter-Glo assay [PMID: 35319895]
ES-2 IC50 787.91 nM Antiproliferative activity against human ES2 cells assessed as cell growth inhibition incubated for 72 hrs by Celltiter-Glo assay [PMID: 35319895]
MDA-MB-468 IC50 405.51 nM Antiproliferative activity against human MDA-MB-468 cells overexpressing wild type EGFR assessed as cell growth inhibition incubated for 72 hrs by Celltiter-Glo assay [PMID: 35319895]
MFE-280 IC50 1291.95 nM Antiproliferative activity against human MFE-280 cells assessed as cell growth inhibition incubated for 72 hrs by Celltiter-Glo assay [PMID: 35319895]
NCI-H441 IC50 1280.72 nM Antiproliferative activity against human NCI-H441 cells assessed as cell growth inhibition incubated for 72 hrs by Celltiter-Glo assay [PMID: 35319895]
NCI-N87 IC50 0.64 nM Antiproliferative activity against human NCI-N87 cells assessed as inhibition of cell growth incubated for 72 hrs by Celltiter-Glo assay [PMID: 35319895]
NUGC-4 IC50 38.15 nM Antiproliferative activity against human NUGC-4 cells assessed as cell growth inhibition incubated for 72 hrs by Celltiter-Glo assay [PMID: 35319895]
Sf9 IC50 2.5 nM Inhibition of human wild type EGFR expressed in Sf9 cells using [gamma32P]-ATP after 10 mins by scintillation counting [PMID: 24900643]
Sf9 IC50 66 nM Inhibition of human EGFR T790M/L858R mutant expressed in Sf9 cells using [gamma32P]-ATP after 10 mins by scintillation counting [PMID: 24900643]
SK-BR-3 IC50 10.34 nM Antiproliferative activity against human SK-BR-3 cells overexpressing wild type HER2 assessed as cell growth inhibition incubated for 72 hrs by Celltiter-Glo assay [PMID: 35319895]
SK-BR-3 IC50 7.2 nM Antiproliferative activity against human SK-BR-3 cells assessed as inhibition of cell proliferation incubated for 3 days by sulforhodamine B colorimetric assay [PMID: 36332549]

13 records · Scroll to view more

In Vitro Studies

Neratinib inhibited the 72-h MTS growth/viability endpoint in H2170, Calu-3 and H1781 cells, with reported IC50 values of 4.7, 16.5 and 13.6 nM, respectively. At 0.1 µM, the three HER2-altered lines showed G1 accumulation after 48 h and increased cleaved PARP in a separate blot readout. Comparable G1 accumulation and increased PARP cleavage were not detected in A549 cells under the reported conditions. [1]

Growth inhibition and pathway suppression in HER2-altered lung cancer cells

Cell-based study · H2170 and Calu-3 (HER2-amplified NSCLC); H1781 (HER2 G776VC-mutant NSCLC). [1]

A concentration-response comparison with erlotinib found low-nanomolar neratinib IC50 values in all three native HER2-altered cell lines. Matched-panel immunoblots showed inhibition of HER2/EGFR phosphorylation and downstream AKT/MAPK phosphorylation. MTS is a metabolic growth/viability endpoint, not a direct binding assay or proof of cell killing.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
H2170 growth inhibitionIC50 4.7 nM (neratinib); 1,150 nM (erlotinib comparator)[1]
Calu-3 growth inhibitionIC50 16.5 nM (neratinib); 316 nM (erlotinib comparator)[1]
H1781 growth inhibitionIC50 13.6 nM (neratinib); 1,080 nM (erlotinib comparator)[1]
HER2, EGFR, AKT and MAPK phosphorylationQualitative immunoblot response Phosphorylation was suppressed with increasing neratinib concentration; total protein and actin controls are shown.[1]

Literature-Reported Treatment Conditions

Treatment concentration
Concentration-response series for MTS; Figure 2B immunoblots show 0, 0.001, 0.01, 0.1, 1 and 10 µM neratinib.
Exposure duration
72 h for MTS; 6 h for pathway immunoblots.
Method
Drug exposure of cultured cells; MTS versus drug-free controls and erlotinib comparator; immunoblots include untreated lanes, total proteins and actin loading control.
Reported limits
In-vitro solvent and its matched vehicle concentration are not specified in the reviewed methods. Exact replicate n and numerical SD for Table I IC50 estimates are not given there; Figure 2A identifies error bars as SD.
Methods and source locations

Compound reported in the paper: Neratinib; Compound label in the paper: Neratinib (HKI-272)

Reported effects concern the paper’s neratinib material and stated models; they do not validate an Adooq lot or establish salt-specific potency.

Table I; Figure 2A,B and caption; Materials and methods: Cell lines and reagents, Cell growth inhibition assay, Western blot analysis; Results: Neratinib inhibits the growth of HER2-amplified and HER2-mutant lung cancer cells (sec14).

H2170 growth inhibition: 72-h modified MTS assay; Table I supplies numerical IC50 values. — Table I, H2170 row; Figure 2A and caption; Cell growth inhibition assay.

Calu-3 growth inhibition: 72-h modified MTS assay; Table I supplies numerical IC50 values. — Table I, Calu-3 row; Figure 2A and caption; Cell growth inhibition assay.

H1781 growth inhibition: 72-h modified MTS assay; Table I supplies numerical IC50 values. — Table I, H1781 row; Figure 2A and caption; Cell growth inhibition assay.

HER2, EGFR, AKT and MAPK phosphorylation: 6-h exposure; Figure 2B dose series. No densitometric percentages or enzyme IC50 values inferred. — Figure 2B and caption; Results sec14 final paragraph; Western blot analysis methods.

Cell-cycle and apoptosis response with an A549 negative comparison

Cell-based study · H2170, Calu-3 and H1781 HER2-altered lung cancer cells compared with KRAS-mutant A549 cells. [1]

Neratinib increased the G1 fraction in the three HER2-altered lines, but a similar increase was not detected in A549. Cleaved-PARP immunoblots supported an apoptotic response in the HER2-altered lines, whereas increased cleavage was not detected in A549. This negative comparison limits generalization to all lung cancer cells.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
G1 fraction among analyzed cells, excluding the sub-G1 fractionDirectional change Increased in H2170, Calu-3 and H1781; similar increase not detected in A549. Figure 3A: mean ± SD, triplicate cultures; *P<0.05 versus non-treated cells.[1]
Cleaved PARP as an apoptosis markerQualitative immunoblot response Increased cleaved PARP in H2170, Calu-3 and H1781; an increase was not detected in A549.[1]

Literature-Reported Treatment Conditions

Treatment concentration
0.1 µM neratinib.
Exposure duration
48 h for cell-cycle analysis; Figure 3B does not separately state the treatment duration for the PARP blot.
Method
Cultured cells exposed to neratinib; non-treated controls. Flow cytometry and cleaved-PARP immunoblotting.
Reported limits
In-vitro drug solvent is not specified in reviewed methods. PARP-blot treatment duration and biological replicate n are not separately specified in the reviewed caption; triplicate cultures apply explicitly to Figure 3A.
Methods and source locations

Compound reported in the paper: Neratinib; Compound label in the paper: Neratinib

Reported effects concern the paper’s neratinib material and stated models; they do not validate an Adooq lot or establish salt-specific potency.

Figure 3A,B and caption; Results: Neratinib induces cell cycle arrest and apoptosis in HER2-dependent cells (sec15); Cell cycle analysis and Western blot analysis methods.

G1 fraction among analyzed cells, excluding the sub-G1 fraction: Propidium iodide flow cytometry after 0.1 µM neratinib for 48 h; doublets, debris and fixation artifacts gated out. — Figure 3A and caption; Results sec15 first two paragraphs; Cell cycle analysis methods.

Cleaved PARP as an apoptosis marker: Figure 3B compares untreated and 0.1 µM neratinib lanes with actin control; exact blot exposure duration is not separately specified in its caption. — Figure 3B and caption; Results sec15 third paragraph; Western blot analysis methods.

In Vivo Studies

In HCC1954 xenografts, neratinib (50 mg/kg) or BCI (50 mg/kg) alone allowed continued tumor growth, whereas their combination suppressed growth during the plotted 18-day follow-up. The study reports n=10 per treatment group. This result concerns the combination in a resistant model; animal dosing route and frequency are not specified in the reviewed sections. [2]

Neratinib plus BCI in HCC1954 xenografts

Animal study · HCC1954 subcutaneous xenografts in 6–8-week-old BALB/cOlaHsd-Foxn1nu mice. [2]

In this HER2-inhibitor-resistant model, neratinib alone and BCI alone did not prevent tumor growth. The combination suppressed tumor growth, with some negative tumor-volume changes in the day-18 waterfall plot. This is combination evidence and does not establish neratinib monotherapy efficacy or a uniquely DUSP6-mediated mechanism.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Tumor volume and percent change from treatment startDirectional combination response Combination inhibited tumor growth relative to control and either monotherapy. Figure 5B: mean ± SD, n=10 per treatment group; ****P<0.0001 for the displayed comparisons. Exact percent inhibition was not extracted.[2]

Conditions shared by the study groups

Treatment course
Plotted follow-up through day 18; actual dosing course not separately specified.
Study groups and reported outcomes
Group / doseComparatorObserved resultReference
Vehicle/controlVehicle/control and both monotherapy comparators in the same HCC1954 experiment.Tumors grew over the plotted follow-up.[2]
Neratinib alone
50 mg/kg		Vehicle/control and both monotherapy comparators in the same HCC1954 experiment.Tumor growth persisted; no strong monotherapy inhibition in this model.[2]
BCI alone
50 mg/kg		Vehicle/control and both monotherapy comparators in the same HCC1954 experiment.Tumor growth persisted; no strong monotherapy inhibition in this model.[2]
Neratinib plus BCI
Neratinib 50 mg/kg plus BCI 50 mg/kg		Vehicle/control and both monotherapy comparators in the same HCC1954 experiment.Suppressed tumor growth relative to control and either monotherapy; some individual tumors had negative volume changes in Figure 5C.[2]
Vehicle/control
Model: HCC1954 xenografts; n=10 per treatment group in Figure 5 caption.
Reported limits: Route, frequency and vehicle composition are unspecified in the reviewed animal sections. Animal sex is not specified in the reviewed animal methods.
Neratinib alone
Model: HCC1954 xenografts; n=10 per treatment group in Figure 5 caption.
Reported limits: Route, frequency and vehicle composition are unspecified in the reviewed animal sections. Animal sex is not specified in the reviewed animal methods.
BCI alone
Model: HCC1954 xenografts; n=10 per treatment group in Figure 5 caption.
Reported limits: Route, frequency and vehicle composition are unspecified in the reviewed animal sections. Animal sex is not specified in the reviewed animal methods.
Neratinib plus BCI
Model: HCC1954 xenografts; n=10 per treatment group in Figure 5 caption.
Reported limits: Route, frequency and vehicle composition are unspecified in the reviewed animal sections. Animal sex is not specified in the reviewed animal methods.
Methods and source locations

Compound reported in the paper: Neratinib; Compound label in the paper: Neratinib alone or with BCI

HCC1954 xenograft combination evidence for the reported neratinib material only; no product-lot validation or salt conversion.

Figure 5B,C and caption (XML Fig9); Results Sec14; Animal studies Sec31; Reagents Sec20.

Tumor volume and percent change from treatment start: Caliper-measured xenograft volume; Figure 5 caption specifies measurement every 3 d and one-way ANOVA followed by Tukey multiple comparisons. Figure 5C shows individual percent changes. — Figure 5B,C and caption (XML Fig9); Results: DUSP6 inhibition overcomes HER2 inhibitor resistance in vivo (Sec14); Animal studies (Sec31).

Vehicle/control · Figure 5B,C and caption; Results Sec14; Animal studies Sec31.

Neratinib alone · Figure 5B,C and caption; Results Sec14; Animal studies Sec31.

BCI alone · Figure 5B,C and caption; Results Sec14; Animal studies Sec31.

Neratinib plus BCI · Figure 5B,C and caption; Results Sec14; Animal studies Sec31.

Specifications

Manufacturer Adooq Bioscience
Actions Inhibitor
CAS Number 698387-09-6
Applications HER2 inhibitor
Formula C30H29ClN6O3
Molecular Weight 557
Synonyms HKI-272
SMILES
CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=CC(=C(C=C3)OCC4=CC=CC=N4)Cl)C#N)NC(=O)/C=C/CN(C)C

Storage & Solubility

In Vitro Solubility

Reported Solubility

SolventReported Solubility
DMSO Warmed: 4 mg/mL (7.18 mM)
Water Insoluble
Ethanol Insoluble

Preparing Stock Solutions

Stock preparation is unavailable for this product molecular weight.

Calculated stock concentrations do not establish solvent solubility. Refer to the reported solubility data for experimental guidance.

In Vivo Preparation

Concentration
4 mg/mL
Vehicle
30% PEG400+0.5% Tween80+5% propylene glycol

Storage

Store powder at -20°C, keep desiccated.
In powder form, the chemical is stable for 36 months.
In solution, store at -20°C and use within 1 month to prevent loss of potency. Aliquot to avoid multiple freeze/thaw cycles.

Research References

  1. [1] Ogoshi Y, Shien K, Yoshioka T, et al. Anti-tumor effect of neratinib against lung cancer cells harboring <i>HER2</i> oncogene alterations. Oncology letters (2019). PMID: 30854046 DOI: 10.3892/ol.2019.9908 Source material
  2. [2] Momeny M, Tienhaara M, Sharma M, et al. DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer. EMBO molecular medicine (2024). PMID: 38886591 DOI: 10.1038/s44321-024-00088-0 Source material

Publications

3 publications citing this product

  1. Majid Momeny, .et al. , EMBO Mol Med, 2024, Jun 17 PMID: 38886591
  2. Hamzehlou S, .et al. , Eur J Pharmacol, 2019, Nov 15;863:172705 PMID: 31574259
  3. Li Li, .et al. , Leukemia Res, 2019, 78:12-20 PMID: 30660961

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