Home Protein Tyrosine Kinase HER2 inhibitor - EGFR inhibitor AC480 (BMS-599626)

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AC480 (BMS-599626) HER2 inhibitor

Cat.No.S1056

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. This compound is in Phase 1.
AC480 (BMS-599626) HER2 inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 530.55

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Chemical Information, Storage & Stability

Molecular Weight 530.55 Formula

C27H27FN8O3

 Storage (From the date of receipt)
CAS No. 714971-09-2 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles CC1=C2C(=NC=NN2C=C1NC(=O)OCC3COCCN3)NC4=CC5=C(C=C4)N(N=C5)CC6=CC(=CC=C6)F

Solubility

In vitro
Batch:

DMSO : 113 mg/mL (212.98 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 20 mg/mL

Water : Insoluble

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Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Targets/IC50/Ki
HER1 [1]
20 nM
HER2 [1]
30 nM
HER4 [1]
190 nM
In vitro
AC480 (BMS-599626) is identified as an ATP-competitive inhibitor for HER1 and as an ATP-noncompetitive inhibitor for HER2 with Ki of 2 nM and 5 nM, respectively. It also inhibits the related receptor HER4, but with reduced potency with IC50 of 190 nM. This compound inhibits the proliferation of tumor cells expressing high levels of HER1 and/or HER2, including Sal2, BT474, N87, KPL-4, HCC202, HCC1954, HCC1419, AU565, ZR-75-30, MDA-MB-175, GEO, and PC9 cells with IC50 of 0.24 μM, 0.31 μM, 0.45 μM, 0.38μM, 0.94 μM, 0.34 μM, 0.75 μM, 0.63 μM, 0.51 μM, 0.84 μM, 0.90 μM and 0.34 μM, respectively. While the proliferation of the ovarian tumor cell line A2780 and MRC5 fibroblasts, neither of which expresses HER1 or HER2, are not inhibited significant by it. [1] A recent study shows that it significantly enhances the radiosensitivity of HN-5 cells expressing both EGFR and Her2 cell, by promoting cycle redistribution and inhibiting DNA repair. [2]
Kinase Assay
Protein kinase assays
The entire cytoplasmic sequences of HER1, HER2, and HER4 are expressed as recombinant proteins in Sf9 insect cells. HER1 and HER4 are expressed as fusion proteins with glutathione-S-transferase and are purified by affinity chromatography on glutathione-S-Sepharose. HER2 is subcloned into the pBlueBac4 vector and expressed as an untagged protein using an internal methionine codon (M687) for translation initiation. The truncated HER2 protein is isolated by chromatography on a column of DEAE-Sepharose equilibrated in a buffer that contains 0.1 M NaCl, and the recombinant protein is eluted with a buffer containing 0.3 M NaCl. For the HER kinase assays, reaction volumes are 50 μL and contains 10 ng of glutathione-S-transferase fusion protein or 150 ng of partially purified HER2. The mixtures also contains 1.5 μM poly(Glu/Tyr) (4:1), 1 μM ATP, 0.15 μCi [γ-33P]ATP, 50 mM Tris-HCl (pH 7.7), 2 mM DTT, 0.1 mg/mL bovine serum albumin, and 10 mM MnCl2. Reactions are allowed to proceed at 27°C for 1 hour and are terminated by the addition of 10 μL of a stop buffer (2.5 mg/mL bovine serum albumin and 0.3 M EDTA), followed by a 108-μL mixture of 3.5 mM ATP and 5% trichloroacetic acid. Acid-insoluble proteins are recovered on GF/C Unifilter plates with a Filtermate harvester. Incorporation of radioactive phosphate into the poly(Glu/Tyr) substrate is determined by liquid scintillation counting. Percent inhibition of kinase activity is determined by nonlinear regression analyses and data are reported as the inhibitory concentration required to achieve 50% inhibition relative to control reactions (IC50). Data are the averages of triplicate determinations. All other tyrosine kinases are also assayed using poly(Glu/Tyr) as a substrate. Kinetics of HER1 and HER2 inhibition are determined in reaction mixtures that contains varying concentrations of ATP and AC480 (BMS-599626).
In vivo
AC480 (BMS-599626) yields a potent antitumor activity in a human breast tumor KPL-4 xenograft at its maximum tolerated dose of 180 mg/kg, and also has similar antitumor activity in other HER2 amplified xenograft models, as well as other HER1-overexpressing xenograft models. In vivo, oral administration of this compound results in a dose-dependent inhibition of Sal2 tumor growth at doses ranging from 60 mg/kg to 240 mg/kg. [1]
References

Clinical Trial Information

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

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01245543 Withdrawn
Solid Tumors
Daiichi Sankyo
 November 2010 Phase 1
NCT00979173 Completed
Glioma
Annick Desjardins|Ambit Biosciences Corporation|Duke University
 November 2009 Phase 1
NCT00093730 Completed
Unspecified Adult Solid Tumor Protocol Specific
Jonsson Comprehensive Cancer Center|National Cancer Institute (NCI)
 August 2004 Phase 1
NCT00095537 Completed
Cancer|Metastases
Bristol-Myers Squibb
 March 2004 Phase 1

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