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AC480 (BMS-599626)

HER1/2 inhibitor,selective and efficacious CAS# 714971-09-2

AC480 (BMS-599626)

Catalog No. BCC1252----Order now to get a substantial discount!

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AC480 (BMS-599626): 5mg $138 In Stock
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Chemical structure

AC480 (BMS-599626)

3D structure

Chemical Properties of AC480 (BMS-599626)

Cas No. 714971-09-2 SDF Download SDF
PubChem ID 10437018 Appearance Powder
Formula C27H27FN8O3 M.Wt 530.6
Type of Compound N/A Storage Desiccate at -20°C
Synonyms AC480
Solubility Soluble to 113 mg/mL (212.98 mM) in DMSO
Chemical Name [(3S)-morpholin-3-yl]methyl N-[4-[[1-[(3-fluorophenyl)methyl]indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamate
SMILES CC1=C2C(=NC=NN2C=C1NC(=O)OCC3COCCN3)NC4=CC5=C(C=C4)N(N=C5)CC6=CC(=CC=C6)F
Standard InChIKey LUJZZYWHBDHDQX-QFIPXVFZSA-N
Standard InChI InChI=1S/C27H27FN8O3/c1-17-23(34-27(37)39-15-22-14-38-8-7-29-22)13-36-25(17)26(30-16-32-36)33-21-5-6-24-19(10-21)11-31-35(24)12-18-3-2-4-20(28)9-18/h2-6,9-11,13,16,22,29H,7-8,12,14-15H2,1H3,(H,34,37)(H,30,32,33)/t22-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of AC480 (BMS-599626)

DescriptionAC480 is a selective and efficacious inhibitor of HER1 and HER2 with IC50 values of 20 nM and 30 nM, respectively.
TargetsHER1HER2    
IC5020 nM30 nM    

AC480 (BMS-599626) Dilution Calculator

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AC480 (BMS-599626) Molarity Calculator

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Preparing Stock Solutions of AC480 (BMS-599626)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.8847 mL 9.4233 mL 18.8466 mL 37.6932 mL 47.1165 mL
5 mM 0.3769 mL 1.8847 mL 3.7693 mL 7.5386 mL 9.4233 mL
10 mM 0.1885 mL 0.9423 mL 1.8847 mL 3.7693 mL 4.7116 mL
50 mM 0.0377 mL 0.1885 mL 0.3769 mL 0.7539 mL 0.9423 mL
100 mM 0.0188 mL 0.0942 mL 0.1885 mL 0.3769 mL 0.4712 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on AC480 (BMS-599626)

AC480 (BMS-599626) is a potent, selective inhibitor of human epidermal growth factor receptor (HER) that inhibits HER1 and HER2 with IC values of 20 nM and 30 nM, respectively. AC480 has been proved to inhibit HER1 in an ATP-competitive manner. On the contrary, AC480 has shown to be an ATP noncompetitive inhibitor of HER2 [1]

AC480 inhibited the proliferation of Sal2 cells derived from a transgenic mouse tumor, breast tumor and gastric carcinoma cell lines, GEO colon tumor cells, non–small-cell lung tumor cells line via HER1 and/or HER2 signalings [1].

AC480 by oral administration has been demonstrated to suppress the growth of Sal2 tumor, GEO xenograft tumor, KPL-4 and BT474 breast tumors, N87 gastric tumor, A549 and L2987 non–small-cell lung tumors in nude mice [1].

References:
[1] Wong TW1, Lee FY, Yu C, Luo FR, Oppenheimer S, Zhang H, Smykla RA, Mastalerz H, Fink BE, Hunt JT,Gavai AV, Vite GD. Preclinical antitumor activity of BMS-599626, a pan-HER kinase inhibitor that inhibits HER1/HER2 homodimer and heterodimer signaling. Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6186-93.

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References on AC480 (BMS-599626)

AC480, formerly BMS-599626, a pan Her inhibitor, enhances radiosensitivity and radioresponse of head and neck squamous cell carcinoma cells in vitro and in vivo.[Pubmed:20119866]

Invest New Drugs. 2011 Aug;29(4):554-61.

PURPOSE: The present study investigated the effect of AC480, a small molecule pan-HER tyrosine kinase inhibitor, on in vitro radiosensitivity and in vivo radioresponse of a human head and neck squamous cell carcinoma cell line. METHODS: HN-5 cells were exposed to gamma-radiation with and without AC480 and assayed for proliferation, clonogenic survival, apoptosis, cell cycle distribution, and DNA damage. The cells were analyzed by immunoprecipitation and western blotting for proteins involved in apoptosis, cell cycle regulation, and the EGFR pathway. The effect of AC480 on tumor radioresponse was assessed by tumor growth delay assay using HN5 tumor xenografts generated in nude mice. RESULTS: At the molecular level, in HN-5 cells the agent inhibited the expression of pEGFR, pHER2, cyclins D and E, pRb, pAkt, pMAPK, pCDK1 and 2, CDK 6, and Ku70 proteins. The drug also induced accumulation of cells in the G1 cell cycle phase, inhibited cell growth, enhanced radiosensitivity, and prolonged the presence of gamma-H(2)AX foci up to 24 h after radiation. AC480 did not increase the percentage of cells undergoing radiation-induced apoptosis. The drug given before and during irradiation improved the radioresponse of HN5 tumors in vivo. CONCLUSION: AC480 significantly enhanced the radiosensitivity of HN-5 cells, expressing both EGFR and Her2. The mechanisms involved in the enhancement included cell cycle redistribution and inhibition of DNA repair. Both in vitro and in vivo data from our study suggest that AC480 has potential to increase tumor response to radiotherapy.

Phase I safety, pharmacokinetic and pharmacodynamic trial of BMS-599626 (AC480), an oral pan-HER receptor tyrosine kinase inhibitor, in patients with advanced solid tumors.[Pubmed:21576284]

Ann Oncol. 2012 Feb;23(2):463-71.

PURPOSE: We studied the safety, tolerability, and recommended dose of BMS-599626, an orally bioavailable inhibitor of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. PATIENTS AND METHODS: Patients with advanced solid tumors that expressed epidermal growth factor receptor (EGFR) and/or HER-2 were recruited and enrolled in a phase I, open-label, dose escalation trial of oral BMS-599626 starting at 100 mg/day given once daily for at least 28 days. RESULTS: Forty-five patients received BMS-599626 (100-660 mg/day). Dose-limiting toxic effects were reported at 660 mg/day (grade 3 elevation of hepatic transaminases [two patients] and QTc interval prolongation [one patient]), therefore the recommended maximum tolerated dose was 600 mg/day. The most frequent drug-related toxic effects were diarrhea (30% of patients), anorexia (13%), asthenia (30%), and cutaneous toxic effects, including skin rash (30%). Pharmacokinetic analysis demonstrated C(max) and exposure to BMS-599626 in patients increased with dose. Eleven patients had stable disease and received BMS-599626 for >/= 4 months. Serial skin and tumor biopsies taken before and after treatment revealed expected changes in pharmacodynamic biomarkers, indicating that the EGFR and HER-2 pathways were affected. Positron emission tomography imaging showed a metabolic response in 2 of 10 patients evaluated. CONCLUSION: BMS-599626 was generally well tolerated, with disease stabilization across a range of tumor types and doses.

Description

BMS-599626 (AC480) is a selective and orally bioavailable HER1 and HER2 inhibitor, with IC50s of 20 and 30 nM, respectively. BMS-599626 displays ~8-fold less potent to HER4 (IC50=190 nM), >100-fold to VEGFR2, c-Kit, Lck, MEK. BMS-599626 inhibits tumor cell proliferation, and has potential to increase tumor response to radiotherapy.

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