WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 200078
CAS#: 873837-23-1 (HCl)
Description: AC480, also known as BMS-599626, is an orally bioavailable inhibitor of the HER1, HER2 and HER4 tyrosine kinases (IC50 =22, 32 and 190 nM, respectively) with potential antineoplastic activity. BMS-599626 inhibits human epidermal growth factor receptors (HER) HER1, HER2 and HER4, thereby inhibiting the proliferation of tumor cells that overexpress these receptors.
MedKoo Cat#: 200078
Name: AC480 HCl
CAS#: 873837-23-1 (HCl)
Chemical Formula: C27H28ClFN8O3
Exact Mass: 566.2
Molecular Weight: 567.02
Elemental Analysis: C, 57.19; H, 4.98; Cl, 6.25; F, 3.35; N, 19.76; O, 8.46
Related CAS #: 873837-23-1 (HCl) 714971-09-2 (free base)
Synonym: AC480; AC-480; AC 480 HCl; AC 480 hydrochloride; BMS599626; BMS-599626; BMS 599626; BMS599626 HCl; BMS599626 hydrochloride.
IUPAC/Chemical Name: (S)-morpholin-3-ylmethyl (4-((1-(3-fluorobenzyl)-1H-indazol-5-yl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)carbamate hydrochloride
InChi Key: COUSSRGSHIJMMN-FTBISJDPSA-N
InChi Code: InChI=1S/C27H27FN8O3.ClH/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);1H/t22-;/m0./s1
SMILES Code: O=C(OC[C@H]1NCCOC1)NC2=CN3N=CN=C(NC4=CC5=C(N(CC6=CC=CC(F)=C6)N=C5)C=C4)C3=C2C.[H]Cl
Appearance: White to off-white solid powder.
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not soluble in water; soluble in 10% HCl solution.
Shelf Life: >2 years if stored properly
Drug Formulation: AC480 free base or AC480HCl are soluble in DMSO, not water soluble in water. AC480 or AC480 HCl salt can be formulated in DMSO.
Stock Solution Storage: 0-4 C for short term (days to weeks), -20 C for long term (weeks to months).
HS Tariff Code: 2934.99.9001
| Biological target: | BMS-599626 Hydrochloride (AC480 Hydrochloride) is a HER1 and HER2 inhibitor, with IC50s of 20 and 30 nM, respectively. |
| In vitro activity: | Treatment with AC480 inhibited EGFR and HER2 receptor phosphorylation and downstream signaling in HN-5 cells. By immunoprecipitation analysis, the agent markedly reduced the phosphorylation of EGFR and HER2 and heterodimerization of the two receptors (Fig. 1). By western blot analysis, AC480 downregulated the expression of pEGFR (y845) (Fig. 1) but had no appreciable effect on the expression of pEGFR (y1173) or pEGFR (y992) or on the expression of pHER2 (y1248) or pHER2 (y877) (data not shown). The radiation-induced phosphorylation of MAPK, a downstream effector molecule within the EGFR pathway, was greatly reduced by AC480 (Fig. 1). Reference: Invest New Drugs. 2011 Aug;29(4):554-61. https://pubmed.ncbi.nlm.nih.gov/20119866/ |
| In vivo activity: | Treatment with AC480 reduced EGF-induced in vivo invasion to background levels (Fig. 2A). To test the ability of AC480 to block intravasation, blood from the right atria of mice carrying MTLn3E or MDA-MB-231 xenograft tumors was collected and numbers of tumor cells per milliliter were scored. This study found that AC480 treatment resulted in a greater than 80% decrease in the number of intravasated MTLn3E (Fig. 2B) or MDA-MB-231 (Fig. 2C) cells. Cells exposed to AC480 for 3 hours showed similar survival post-treatment to DMSO controls (Fig. 2D), demonstrating that the effect of AC480 on intravasation was not due to altered cell survival. In order to confirm that the observed effects of AC480 treatment are caused by ERBB inhibition and not by off-target effects, this study treated tumor bearing animals with a different ERBB1 and ERBB2 inhibitor, lapatinib (GW572016). Lapatinib treatment also significantly reduced intravasation of tumor cells (Fig. 2B), indicating that the inhibition of intravasation reflects inhibition of ERBB signaling. Reference: Clin Cancer Res. 2009 Jun 1; 15(11): 3733–3739. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859965/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 100.0 | 176.36 |
The following data is based on the product molecular weight 567.02 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Torres MA, Raju U, Molkentine D, Riesterer O, Milas L, Ang KK. 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. Invest New Drugs. 2011 Aug;29(4):554-61. doi: 10.1007/s10637-010-9389-3. Epub 2010 Feb 2. PMID: 20119866. 2. Becker MA, Farzan T, Harrington SC, Krempski JW, Weroha SJ, Hou X, Kalli KR, Wong TW, Haluska P. Dual HER/VEGF receptor targeting inhibits in vivo ovarian cancer tumor growth. Mol Cancer Ther. 2013 Dec;12(12):2909-16. doi: 10.1158/1535-7163.MCT-13-0547. Epub 2013 Oct 15. PMID: 24130056; PMCID: PMC3880137. 3. Kedrin D, Wyckoff J, Boimel PJ, Coniglio SJ, Hynes NE, Arteaga CL, Segall JE. ERBB1 and ERBB2 have distinct functions in tumor cell invasion and intravasation. Clin Cancer Res. 2009 Jun 1;15(11):3733-9. doi: 10.1158/1078-0432.CCR-08-2163. Epub 2009 May 19. PMID: 19458057; PMCID: PMC2859965. |
| In vitro protocol: | 1. Torres MA, Raju U, Molkentine D, Riesterer O, Milas L, Ang KK. 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. Invest New Drugs. 2011 Aug;29(4):554-61. doi: 10.1007/s10637-010-9389-3. Epub 2010 Feb 2. PMID: 20119866. |
| In vivo protocol: | 1. Becker MA, Farzan T, Harrington SC, Krempski JW, Weroha SJ, Hou X, Kalli KR, Wong TW, Haluska P. Dual HER/VEGF receptor targeting inhibits in vivo ovarian cancer tumor growth. Mol Cancer Ther. 2013 Dec;12(12):2909-16. doi: 10.1158/1535-7163.MCT-13-0547. Epub 2013 Oct 15. PMID: 24130056; PMCID: PMC3880137. 2. Kedrin D, Wyckoff J, Boimel PJ, Coniglio SJ, Hynes NE, Arteaga CL, Segall JE. ERBB1 and ERBB2 have distinct functions in tumor cell invasion and intravasation. Clin Cancer Res. 2009 Jun 1;15(11):3733-9. doi: 10.1158/1078-0432.CCR-08-2163. Epub 2009 May 19. PMID: 19458057; PMCID: PMC2859965. |
1: Soria JC, Cortes J, Massard C, Armand JP, De Andreis D, Ropert S, Lopez E, Catteau A, James J, Marier JF, Beliveau M, Martell RE, Baselga J. 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. Ann Oncol. 2012 Feb;23(2):463-71. doi: 10.1093/annonc/mdr137. Epub 2011 May 16. PubMed PMID: 21576284.
2: Torres MA, Raju U, Molkentine D, Riesterer O, Milas L, Ang KK. 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. Invest New Drugs. 2011 Aug;29(4):554-61. doi: 10.1007/s10637-010-9389-3. Epub 2010 Feb 2. PubMed PMID: 20119866.
3: Gavai AV, Fink BE, Fairfax DJ, Martin GS, Rossiter LM, Holst CL, Kim SH, Leavitt KJ, Mastalerz H, Han WC, Norris D, Goyal B, Swaminathan S, Patel B, Mathur A, Vyas DM, Tokarski JS, Yu C, Oppenheimer S, Zhang H, Marathe P, Fargnoli J, Lee FY, Wong TW, Vite GD. Discovery and preclinical evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4 ]triazin-6-yl]carbamic acid, (3S)-3-morpholinylmethyl ester (BMS-599626), a selective and orally efficacious inhibitor of human epidermal growth factor receptor 1 and 2 kinases. J Med Chem. 2009 Nov 12;52(21):6527-30. doi: 10.1021/jm9010065. PubMed PMID: 19821562.
4: Haluska P, Carboni JM, TenEyck C, Attar RM, Hou X, Yu C, Sagar M, Wong TW, Gottardis MM, Erlichman C. HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924. Mol Cancer Ther. 2008 Sep;7(9):2589-98. doi: 10.1158/1535-7163.MCT-08-0493. Epub 2008 Sep 2. PubMed PMID: 18765823; PubMed Central PMCID: PMC2614316.
5: Wong TW, 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. PubMed PMID: 17062696.
6: Albanell J, Gascón P. Small molecules with EGFR-TK inhibitor activity. Curr Drug Targets. 2005 May;6(3):259-74. Review. PubMed PMID: 15857287.
