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Neratinib (HKI-272) HER2/EGFR Inhibitor

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

Kat.nr.: S2150

Neratinib är en mycket selektiv HER2- och EGFR-hämmare med IC50 på 59 nM och 92 nM i cellfria analyser; hämmar svagt KDR och Src, ingen signifikant hämning av Akt, CDK1/2/4, IKK-2, MK-2, PDK1, c-Raf och c-Met. Fas 3.

Neratinib (HKI-272) HER2 Inhibitor Chemical Structure

Kemisk struktur

Molekylvikt: 557.04

Hoppa till

Kvalitetskontroll (Quality Control)

Batch: Renhet: 99.94%

99.94

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

Cellodling, behandling & arbetskoncentration
(Cell Culture, Treatment & Working Concentration)

Cellinjer	Analystyp	Koncentration	Inkubationstid	Aktivitetsbeskrivning	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
Klicka för att visa mer experimentella data för cellinjer

Kemisk information, lagring & stabilitet (Chemical Information, Storage & Stability)

Molekylvikt	557.04	Formel	C₃₀H₂₉ClN₆O₃	Lagring (från mottagningsdatumet)	3 år-20°Cpulver
CAS-nr	698387-09-6	Ladda ner SDF		Lagring av stamlösningar	1 år-80°Ci lösningsmedel 1 månad-20°Ci lösningsmedel
Synonymer	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

Löslighet (Solubility)

In vitro
Batch:

DMSO : 6 mg/mL (10.77 mM)
(Fuktkontaminerad DMSO kan minska lösligheten. Använd färk, vattenfri DMSO.)

Water : Insoluble

Ethanol : Insoluble

DMSO : 7 mg/mL (12.56 mM) Uppvärmd med 60°C vattenbad; Ultraljudsbehandlad;
(Fuktkontaminerad DMSO kan minska lösligheten. Använd färk, vattenfri DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molaritetsräknare

Massa	Koncentration	Volym	Molekylvikt
=	×	×

Utspädningsräknare Molekylviktsräknare

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 Validerad av Selleck-laboratorier. Om du behöver justeringar av denna formulering, kontakta vårt säljteam för skräddarsydd testning.	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-formuleringsräknare (Klar lösning)

Steg 1: Ange information nedan (Rekommenderas: Ett extra djur för att ta hänsyn till förluster under experimentet)

Dosering: mg/kg Djurens medelvikt: g Doseringsvolym per djur:μL Antal djur:

Steg 2: Ange in vivo-formuleringen (Detta är endast räknaren, inte formuleringen. Vänligen kontakta oss först om det inte finns någon in vivo-formulering i löslighetsavsnittet.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Beräkningsresultat:

Arbetskoncentration: mg/ml;

Metod för att bereda DMSO-stamlösning: mg substans förlöst i μL DMSO ( Stamlösningskoncentration mg/mL, Vänligen kontakta oss först om koncentrationen överskrider DMSO-lösligheten för denna batch av substansen. )

Metod för att bereda in vivo-formulering: Ta μL DMSO stamlösning, tillsätt sedanμL PEG300, blanda och klarna, tillsätt sedanμL Tween 80, blanda och klarna, tillsätt sedan μL ddH₂O, blanda och klarna.

Metod för att bereda in vivo-formulering: Ta μL DMSO stamlösning, tillsätt sedan μL Majsolja, blanda och klarna.

Obs: 1. Se till att vätskan är klar innan du tillsätter nästa lösningsmedel.
2. Se till att tillsätta lösningsmedlet/lösningsmedlen i ordning. Du måste se till att lösningen som erhålls i föregående tillsats är en klar lösning innan du fortsätter att tillsätta nästa lösningsmedel. Fysiska metoder som vortex, ultraljud eller varmt vattenbad kan användas för att underlätta upplösningen.

Verkningsmekanism (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.
Kinasanalys	Cellfritt autofosforyleringstest med tidsupplöst fluorometri
Kinasanalys	Neratinib bereds som 10 mg/mL stamlösningar i DMSO och späds i 25 mM HEPES (pH 7,5; 0,002 ng/mL-20 μg/mL). Renade rekombinanta COOH-terminala fragment av HER2 (aminosyror 676-1255) eller epidermal tillväxtfaktorreceptor (EGFR) (aminosyror 645-1186) [utspädda i 100 mM HEPES (pH 7,5) och 50 % glycerol] inkuberas med ökande koncentrationer av denna förening i 4 mM HEPES (pH 7,5), 0,4 mM MnCl₂, 20 μM natriumvanadat och 0,2 mM DTT i 15 minuter vid rumstemperatur i 96-brunns ELISA-plattor. Kinaskektionen initieras genom tillsats av 40 μM ATP och 20 mM MgCl₂ och får fortgå i 1 timme vid rumstemperatur. Plattorna tvättas, och fosforylering detekteras med Europium-märkta anti-fosfo-tyrosinantikroppar (15 ng/brunn). Efter tvätt- och förstärkningssteg detekteras signal med en Victor2-fluorescensläsare (excitationvåglängd 340 nm, emissionsvåglängd 615 nm). Koncentrationen av denna kemikalie som hämmar receptorfosforylering med 50 % (IC50) beräknas från inhibitionskurvor.
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.
Referenser	[1] https://pubmed.ncbi.nlm.nih.gov/15173008/

Applikationer (Applications)

Metoder	Biomarkörer	Bilder	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

Klinisk prövningsinformation (Clinical Trial Information)

(data från https://clinicaltrials.gov, uppdaterad den 2024-05-22)

NCT-nummer	Rekrytering	Tillstånd	Sponsor/Samarbetspartners	Startdatum	Faser
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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