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Neratinib (HKI-272) HER2/EGFR-remmer

Name: Neratinib (HKI-272)
Brand: Selleck Chemicals
SKU: S2150
Rating: 5 (110 reviews)

Cat.Nr.: S2150

Neratinib is een zeer selectieve HER2- en EGFR-remmer met een IC50 van 59 nM en 92 nM in celvrije assays; het remt zwak KDR en Src, geen significante remming van Akt, CDK1/2/4, IKK-2, MK-2, PDK1, c-Raf en c-Met. Fase 3.

Neratinib (HKI-272) HER2 Remmer Chemical Structure

Chemische structuur

Moleculair gewicht: 557.04

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Kwaliteitscontrole (Quality Control)

Batch: Zuiverheid: 99.94%

99.94

Gerelateerde doelwitten	EGFR VEGFR FGFR PDGFR c-Met Src MEK CSF-1R FLT3 c-Kit
Overige HER2 Inhibitoren	Sevabertinib (BAY 2927088) CP-724714 Sapitinib (AZD8931) Mubritinib (TAK 165) AC480 (BMS-599626) Tyrphostin AG 879 HER2-Inhibitor-1 TAS0728 Zongertinib (BI 1810631) IAM1363

Celkweek, behandeling & werkconcentratie
(Cell Culture, Treatment & Working Concentration)

Cellijnen	Assaytype	Concentratie	Incubatietijd	Activiteitsbeschrijving	PMID
BT-474	Growth Inhibition Assay			IC50<0.005 μM	24009064
EFM-192A	Growth Inhibition Assay			IC50<0.005 μM	24009064
HCC1569	Growth Inhibition Assay			IC50<0.005 μM	24009064
HCC1954	Growth Inhibition Assay			IC50<0.005 μM	24009064
MDA-MB-175	Growth Inhibition Assay			IC50<0.005 μM	24009064
MDA-MB-361	Growth Inhibition Assay			IC50<0.005 μM	24009064
SK-BR-3	Growth Inhibition Assay			IC50<0.005 μM	24009064
UACC-812	Growth Inhibition Assay			IC50<0.005 μM	24009064
UACC-893	Growth Inhibition Assay			IC50<0.005 μM	24009064
SUM-225	Growth Inhibition Assay			IC50=0.01 μM	24009064
SUM-190	Growth Inhibition Assay			IC50=0.01 μM	24009064
ZR-75-1	Growth Inhibition Assay			IC50=0.03 μM	24009064
HCC70	Growth Inhibition Assay			IC50=0.03 μM	24009064
BT-20	Growth Inhibition Assay			IC50=0.07 μM	24009064
MDA-MB-453	Growth Inhibition Assay			IC50=0.09 μM	24009064
HCC1187	Growth Inhibition Assay			IC50=0.10 μM	24009064
EFM-19	Growth Inhibition Assay			IC50=0.11 μM	24009064
T-47D	Growth Inhibition Assay			IC50=0.16 μM	24009064
MDA-MB-134	Growth Inhibition Assay			IC50=0.17 μM	24009064
HCC38	Growth Inhibition Assay			IC50=0.25 μM	24009064
MDA-MB-435	Growth Inhibition Assay			IC50=0.33 μM	24009064
MDA-MB-468	Growth Inhibition Assay			IC50=0.33 μM	24009064
CAMA-1	Growth Inhibition Assay			IC50=0.37 μM	24009064
MDA-MB-436	Growth Inhibition Assay			IC50=0.41 μM	24009064
MCF-7	Growth Inhibition Assay			IC50=0.41 μM	24009064
MDA-MB-415	Growth Inhibition Assay			IC50=0.42 μM	24009064
HCC1806	Growth Inhibition Assay			IC50=0.44 μM	24009064
HCC1395	Growth Inhibition Assay			IC50=0.49 μM	24009064
HCC1937	Growth Inhibition Assay			IC50=0.50 μM	24009064
HCC1143	Growth Inhibition Assay			IC50=0.54 μM	24009064
UACC-732	Growth Inhibition Assay			IC50=0.65 μM	24009064
MDA-MB-231	Growth Inhibition Assay			IC50=1.00 μM	24009064
MDA-MB-157	Growth Inhibition Assay			IC50=1.12 μM	24009064
BT-549	Growth Inhibition Assay			IC50=1.14 μM	24009064
KPL-1	Growth Inhibition Assay			IC50=1.89 μM	24009064
CAL-51	Growth Inhibition Assay			IC50=1.89 μM	24009064
BT474	Growth Inhibition Assay			IC50=0.00323 ± 0.00075 μM	23816254
SKBR3	Growth Inhibition Assay			IC50=0.0075 ± 0.005 μM	23816254
MDAMB453	Growth Inhibition Assay			IC50=1.59 ± 0.179 μM	23816254
KB	Growth Inhibition Assay			IC50=4.13 ± 0.47 μM	22491935
KBv200	Growth Inhibition Assay			IC50=6.03 ± 0.64 μM	22491935
MCF-7	Growth Inhibition Assay			IC50=3.30 ± 0.41 μM	22491935
MCF-7/Adr	Growth Inhibition Assay			IC50= 2.88 ± 0.30 μM	22491935
MCF-7	Growth Inhibition Assay			IC50=3.02 ± 0.34 μM	22491935
MCF-7/FLV1000	Growth Inhibition Assay			IC50=7.09 ± 0.71 μM	22491935
HL60	Growth Inhibition Assay			IC50=2.26 ± 0.23 μM	22491935
HL60/Adr	Growth Inhibition Assay			IC50=1.42 ± 0.15 μM	22491935
HEK293/pcDNA3.1	Growth Inhibition Assay			IC50=5.29 ± 0.53 μM	22491935
HEK293/ABCB1	Growth Inhibition Assay			IC50=6.91 ± 0.70 μM	22491935
SKBR	Growth Inhibition Assay	0.01-100 nM	3-7 d	inhibits cell growth in time and dose dependent manner	21487605
L858R(EGFR)	Cell Viability Assay			decreases cell viability in time and dose dependent manner	17311002
L858R/T790M(EGFR)	Cell Viability Assay			decreases cell viability in time and dose dependent manner	17311002
G776insV_G/C	Cell Viability Assay			decreases cell viability in time and dose dependent manner	17311002
wild-type	Cell Viability Assay			decreases cell viability in time and dose dependent manner	17311002
A775insYVMA	Cell Viability Assay			decreases cell viability in time and dose dependent manner	17311002
G776insV_G/L	Cell Viability Assay			decreases cell viability in time and dose dependent manner	17311002
P780insGSP	Cell Viability Assay			decreases cell viability in time and dose dependent manner	17311002
NCI-H1781	Growth Inhibition Assay			inhibits cell growth in time and dose dependent manner	16818618
HCC827	Growth Inhibition Assay			inhibits cell growth in time and dose dependent manner	16818618
H3255	Growth Inhibition Assay			inhibits cell growth in time and dose dependent manner	16818618
NCI-H1975	Growth Inhibition Assay			inhibits cell growth in time and dose dependent manner	16818618
A549	Growth Inhibition Assay			inhibits cell growth in time and dose dependent manner	16818618
3T3	Growth Inhibition Assay			IC50=700 ± 78 nM	15173008
3T3/neu	Growth Inhibition Assay			IC50=3 ± 0.14 nM	15173008
SK-Br-3	Growth Inhibition Assay			IC50=2 ± 0.18 nM	15173008
BT 474	Growth Inhibition Assay			IC50=2 ± 0.06 nM	15173008
A431	Growth Inhibition Assay			IC50=81 ± 9 nM	15173008
MDA-MB-435	Growth Inhibition Assay			IC50=960 ± 165 nM	15173008
SW620	Growth Inhibition Assay			IC50=690 ± 84 nM	15173008
SKBR3	Function assay			Inhibition of human Her2 in SKBR3 cells, EC50 = 0.002 μM.	18077425
BT474	Function assay			Inhibition of human Her2 in BT474 cells, EC50 = 0.002 μM.	18077425
A431	Function assay			Inhibition of human Her2 in A431 cells, EC50 = 0.081 μM.	18077425
SW620	Function assay			Inhibition of human Her2 in SW620 cells, EC50 = 0.69 μM.	18077425
BA/F3	Cytotoxicity assay			Cytotoxicity against mouse BA/F3 cells expressing EGFR L858R mutant, IC50 = 0.0035 μM.	19239229
BA/F3	Cytotoxicity assay			Cytotoxicity against mouse BA/F3 cells expressing EGFR L858R/T790M mutant, IC50 = 0.18 μM.	19239229
Sf9	Function assay		10 mins	Inhibition of human wild type EGFR expressed in Sf9 cells using [gamma32P]-ATP after 10 mins by scintillation counting, IC50 = 0.0025 μM.	24900643
Sf9	Function assay		10 mins	Inhibition of human EGFR T790M/L858R mutant expressed in Sf9 cells using [gamma32P]-ATP after 10 mins by scintillation counting, IC50 = 0.066 μM.	24900643
BAF3	Function assay		72 hrs	Inhibition of Tel-fused IGF1R (unknown origin) expressed in mouse BAF3 cells assessed as growth inhibition after 72 hrs by CellTiter-Glo assay, GI50 = 0.19 μM.	28282122
BAF3	Function assay		72 hrs	Inhibition of Tel-fused INSR (unknown origin) expressed in mouse BAF3 cells assessed as growth inhibition after 72 hrs by CellTiter-Glo assay, GI50 = 0.29 μM.	28282122
BAF3	Growth inhibition assay		72 hrs	Growth inhibition of mouse BAF3 cells after 72 hrs by CellTiter-Glo assay, GI50 = 1.9 μM.	28282122
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Chemische informatie, Opslag en Stabiliteit (Chemical Information, Storage & Stability)

Moleculair gewicht	557.04	Formule	C₃₀H₂₉ClN₆O₃	Opslag (Vanaf de ontvangstdatum)	3 jaar-20°Cpoeder
CAS-nr.	698387-09-6	SDF downloaden		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	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=CCN(C)C

Oplosbaarheid (Solubility)

In vitro
Batch:

DMSO : 6 mg/mL (10.77 mM)
(Met vocht verontreinigde DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Water : Insoluble

Ethanol : Insoluble

DMSO : 7 mg/mL (12.56 mM) Verwarmd met 60°C waterbad; Geultrasoneerd;
(Met vocht verontreinigde DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molariteitscalculator

Massa	Concentratie	Volume	Moleculair gewicht
=	×	×

Verdunningscalculator Moleculair gewicht calculator

In vivo Batch:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	30%PEG400 1 0.5%Tween80 2 5%propylene glycol Gevalideerd door Selleck labs. Mocht u aanpassingen aan deze formulering nodig hebben, neem dan contact op met ons verkoopteam voor aangepaste tests.	5.000mg/ml (8.98mM)	Taking the 1 mL working solution as an example, add 300 μL of 16.67 mg/ml clarified PEG400 stock solution to 5 μL of Tween80, mix evenly to clarify it; add 50 μL Propylene glycol to the above system, mix evenly to clarify it; then continue to add 645 μL ddH2O Dilute to 1 mL. The mixed solution should be used immediately for optimal results.

In vivo Formuleringscalculator (Heldere oplossing)

Stap 1: Voer de onderstaande informatie in (Aanbevolen: Een extra dier voor het geval van verlies tijdens het experiment)

Dosering: mg/kg Gemiddeld gewicht van dieren: g Doseervolume per dier:μL Aantal dieren:

Stap 2: Voer de in vivo formulering in (Dit is alleen de calculator, geen formulering. Neem eerst contact met ons op als er geen in vivo formulering is in het gedeelte Oplosbaarheid.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Berekeningsresultaten:

Werkconcentratie: mg/ml;

Methode voor het bereiden van DMSO-mastervloeistof: mg geneesmiddel vooraf opgelost in μL DMSO ( Concentratie mastervloeistof mg/mL, Neem eerst contact met ons op als de concentratie de DMSO-oplosbaarheid van de partij geneesmiddel overschrijdt. )

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toeμL PEG300, mengen en helder maken, voeg vervolgens toeμL Tween 80, mengen en helder maken, voeg vervolgens toe μL ddH₂O, mengen en helder maken.

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toe μL Maïsolie, mengen en helder maken.

Opmerking: 1. Zorg ervoor dat de vloeistof helder is voordat u het volgende oplosmiddel toevoegt.
2. Zorg ervoor dat u het/de oplosmiddel(en) in de juiste volgorde toevoegt. U moet ervoor zorgen dat de verkregen oplossing, bij de vorige toevoeging, een heldere oplossing is voordat u verdergaat met het toevoegen van het volgende oplosmiddel. Fysische methoden zoals vortexen, echografie of een warmwaterbad kunnen worden gebruikt om het oplossen te bevorderen.

Werkingsmechanisme (Mechanism of Action)

Targets/IC₅₀/Ki	HER2 (Cell-free assay) 59 nM EGFR (Cell-free assay) 92 nM KDR (Cell-free assay) 800 nM Src (Cell-free assay) 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. This compound 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. It 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. This chemical also inhibits the proliferation of EGFR-dependent A431 cells with an IC50 of 81 nM. It 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 this compound results in inhibition of downstream MAPK and Akt pathways with IC50 of 2 nM, more potently than Trastuzumab. It 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.
Kinase Assay	Celvrije autofosforyleringsassay met behulp van tijdsopgeloste fluorometrie
Kinase Assay	Neratinib wordt bereid als 10 mg/mL stamoplossingen in DMSO en verdund in 25 mM HEPES (pH 7,5; 0,002 ng/mL-20 μg/mL). Gezuiverde recombinante COOH-terminale fragmenten van HER2 (aminozuren 676-1255) of epidermale groeifactorreceptor (EGFR) (aminozuren 645-1186) [verdund in 100 mM HEPES (pH 7,5) en 50% glycerol] worden geïncubeerd met toenemende concentraties van deze verbinding in 4 mM HEPES (pH 7,5), 0,4 mM MnCl₂, 20 μM natriumvanadaat en 0,2 mM DTT gedurende 15 minuten bij kamertemperatuur in 96-well ELISA-platen. De kinasereactie wordt geïnitieerd door de toevoeging van 40 μM ATP en 20 mM MgCl₂ en gedurende 1 uur bij kamertemperatuur voortgezet. Platen worden gewassen en fosforylering wordt gedetecteerd met Europium-gelabelde anti-fosfo-tyrosine-antilichamen (15 ng/well). Na was- en versterkingsstappen wordt het signaal gedetecteerd met een Victor2-fluorescentielezer (excitatiegolflengte 340 nm, emissiegolflengte 615 nm). De concentratie van deze chemische stof die de receptorfosforylering met 50% remt (IC50) wordt berekend uit de remmingscurven.
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, this compound inhibits the growth of BT474 xenografts by 70-82%, 67%, and 93% at dose of 5, 10, and 40 mg/kg/day, respectively. It is also effective against SK-OV-3 xenografts with inhibition of 31% and 85% at 5 and 60 mg/kg/day, respectively. This chemical 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. It 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 it has selective activity for cells expressing HER-2 or EGFR.
Referenties	[1] https://pubmed.ncbi.nlm.nih.gov/15173008/

Toepassingen (Applications)

Methoden	Biomarkers	Afbeeldingen	PMID
Western blot	p-ERBB2 / ERBB2 / p-ERBB3 / ERBB3 / p-EGFR / p-90RSK pHER2 / HER2 / pAKT / AKT / pERK / ERK		30118499
Growth inhibition assay	Cell viability		30118499

Informatie klinische proef (Clinical Trial Information)

(gegevens van https://clinicaltrials.gov, bijgewerkt op 2024-05-22)

NCT-nummer	Rekrutering	Aandoeningen	Sponsor/Medewerkers	Startdatum	Fasen
NCT05388149	Recruiting	Breast Cancer\|HER2-positive Breast Cancer	University Health Network Toronto	December 6 2022	Phase 2
NCT05252988	Recruiting	Early-stage Breast Cancer\|HER2 Positive Breast Cancer\|Hormone Receptor Positive	Spanish Breast Cancer Research Group\|Puma Biotechnology Inc.\|Pierre Fabre Laboratories	August 31 2022	Phase 2
NCT04856475	Withdrawn	Breast Cancer\|Brain Metastases	Jules Bordet Institute	November 24 2021	Phase 2
NCT04781374	Withdrawn	Metastatic Prostate Adenocarcinoma\|Castration-resistant Prostate Cancer\|Prostate Cancer\|Prostate Cancer Metastatic	Beth Israel Deaconess Medical Center\|Puma Biotechnology Inc.\|Dana-Farber Cancer Institute	May 21 2021	Phase 2

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