Home Protein Tyrosine Kinase EGFR inhibitor - HER2 inhibitor - VEGFR inhibitor - FLT inhibitor AEE788 (NVP-AEE788)

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AEE788 (NVP-AEE788) EGFR inhibitor

Cat.No.S1486

AEE788 (NVP-AEE788) is a potent inhibitor of EGFR and HER2/ErbB2 with IC50 of 2 nM and 6 nM, respectively. It is less potent against VEGFR2/KDR, c-Abl, c-Src, and Flt-1, and does not inhibit Ins-R, IGF-1R, PKCα, or CDK1. This compound has reached Phase 1/2 clinical trials.
AEE788 (NVP-AEE788) EGFR inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 440.58

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Quality Control

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
Huh7 Cytotoxicity assay Cytotoxicity against human hepatocellular carcinoma cell line (Huh7), CC50=27.83 Μm
Jeko B cells Function assay 2 h Inhibition of PI3Kdelta in human Jeko B cells assessed as inhibition of Akt phosphorylation after 2 hrs, IC50=0.017 μM
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Chemical Information, Storage & Stability

Molecular Weight 440.58 Formula

C27H32N6

 Storage (From the date of receipt)
CAS No. 497839-62-0 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles CCN1CCN(CC1)CC2=CC=C(C=C2)C3=CC4=C(N3)N=CN=C4NC(C)C5=CC=CC=C5

Solubility

In vitro
Batch:

DMSO : 88 mg/mL (199.73 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Targets/IC50/Ki
EGFR [1]
(Cell-free assay)
2 nM
HER2/ErbB2 [1]
(Cell-free assay)
6 nM
c-Abl [1]
(Cell-free assay)
52 nM
FLT1 [1]
(Cell-free assay)
59 nM
c-Fms [1]
(Cell-free assay)
60 nM
c-Src [1]
(Cell-free assay)
61 nM
KDR [1]
(Cell-free assay)
77 nM
HER4/ErbB4 [1]
(Cell-free assay)
160 nM
In vitro
AEE788 (NVP-AEE788) also inhibits KDR, c-abl, c-Src, and Flt-1 with IC50 of 50-80 nM. It is not sensitive to ErbB-4, PDGFR-β, Flt-3, Flt-4, RET, and c-Kit and has no inhibitory to Ins-R, IGF-1R, PKC-α, and PKA. This compound potently inhibits EGFR phosphorylation in A431 cells with IC50 of 11 nM. It also inhibits the phosphorylation of KDR in CHO cells and erbB2 in BT-474 cells, without any effects on PDGF-induced phosphorylation in A31 cells. It inhibits the proliferation of NCI-H596, MK, BT-474 and SK-BR-3 cells with IC50 of 78, 56, 49 and 381 nM, respectively. Otherwise, it has the additional property of inhibiting cellular proliferation driven by EGFR mutant including 32D/EGFR and 32D/EGFRvIII. It further also inhibits both EGF- and VEGF-driven HUVEC proliferation with IC50 of 43 and 155 nM, respectively. [1] It inhibits the phosphorylation of EGFR, VEGFR2, Akt, and MAPK in human cutaneous SCC cell lines (Colo16, HaCaT, SRB1, and SRB12 cells), which leads to growth inhibition and induction of apoptosis. [2] It inhibits the phosphorylation of EGFR and Akt in HT29 cells at 0.2 to 1.0 μM. [3] It inhibits cell proliferation and prevents EGF- and neuregulin-induced HER1, HER2, and HER3 activation in medulloblastoma cell lines. It shows growth-suppressive activities in chemosensitive and chemoresistant medulloblastoma cells. [4]
Kinase Assay
Protein Kinase Assays
The in vitro kinase assays for AEE788 (NVP-AEE788) are performed in 96-well plates (30 μL) at ambient temperature for 15–45 min using the recombinant glutathione S-transferase-fused kinase domains (4-100 ng, depending on specific activity). [γ33P]ATP is used as phosphate donor and polyGluTyr-(4:1) peptide as acceptor. With the exception of protein kinase C-α, cyclin-dependent kinase 1/cycB and protein kinase A are protamine sulfate (200 μg/mL), histone H1 (100 μg/mL), and the heptapeptide Leu-Arg-Arg-Ala-Ser-Leu-Gly (known as Kemptide Bachem) respectively and are used as peptide substrates. Assays are optimized for each kinase using the following ATP concentrations: 1.0 μM (c-Kit, c-Met, c-Fms, c-Raf-1, and RET), 2.0 μM (EGFR, erbB2, ErbB3, and ErbB4), 5.0 μM (c-abl), 8.0 μM (Flt-1, Flt-3, Flt-4, Flk, KDR, FGFR-1, and Tek), 10.0 μM (PDGFR-β, protein kinase C-α, and cyclin-dependent kinase 1), and 20.0 μM (c-Src and protein kinase A). The reaction is terminated by the addition of 20 μL 125 mM EDTA. Thirty μL (c-abl, c-Src, insulin-like growth factor-1R, RET-Men2A, and RET-Men2B) or 40 μL (all other kinases) of the reaction mixture is transferred onto Immobilon-polyvinylidene difluoride membrane, presoaked with 0.5% H3PO4 and mounted on a vacuum manifold. Vacuum is then applied and each well rinsed with 200 μL 0.5% H3PO4. Membranes are removed and washed four times with 1.0% H3PO4 and once with ethanol. Dried membranes are counted after mounting in a Packard TopCount 96-well frame and with the addition of 10 μL/well of Microscint. IC50 values (±SE) are calculated by linear regression analysis of the percentage inhibition and are averages of at least three determinations.
In vivo
AEE788 (NVP-AEE788) produces a dose-dependent inhibition of tumor growth in NCI-H596 or DU145 xenograft models, with only minor body weight changes. It induces tumor regression by 57% at 50 mg/kg in the NeuT/erbB2 GeMag model and potently inhibits EGF-induced EGFR phosphorylation in A431 tumors and erbB2 phosphorylation in GeMag tumors. This compound dose-dependently inhibited angiogenesis induced by VEGF and does not inhibit bFGF-induced angiogenesis. [1] It suppresses the growth of tumor volume by 54% in Colo16 xenografts at 50 mg/kg, which is due to the inhibition of phosphorylation of EGFR, VEGFR, Akt, and MAPK. [2] At 50 mg/kg, it also inhibits growth of tumors in the cecum and peritoneum (>50%) and reduces the incidence of lymph node metastasis to 70% in HT29 cells implanted in the cecum of nude mice, without loss of body weight and gross evidence of neovascularization. It significantly lowers the expression levels of pEGFR and pVEGFR in HT29 cecal tumors and does not alter those of EGF, VEGF, EGFR, or VEGFR. Combined with CPT-11, it results in significantly smaller tumors and complete inhibition of lymph node metastasis. [3] This compound inhibits the growth of Daoy, DaoyPt, and DaoyHER2 xenografts by 51%, 45%, and 72%, respectively. [4] It could promote LBH589-mediated generation of reactive oxygen species in K562 tumor cells, which in turn increase apoptosis. [5]
References
  • [4] https://pubmed.ncbi.nlm.nih.gov/20885895/
  • [5] https://pubmed.ncbi.nlm.nih.gov/17317822/

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00107237 Completed
Brain and Central Nervous System Tumors
Novartis Pharmaceuticals|Novartis
 October 2003 Phase 1|Phase 2
NCT00118456 Completed
Cancer
Novartis Pharmaceuticals|Novartis
 July 2003 Phase 1

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