AC480 HCl (also known as BMS-599626 HCl) is a novel, potent, orally bioavailable, selective and efficacious inhibitor of HER1 and HER2 (human epidermal growth factor receptors) with IC50 of 20 nM and 30 nM, ~8-fold less potent to HER4, >100-fold to VEGFR2, c-Kit, Lck, MET etc. 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.
Physicochemical Properties
| Molecular Formula | C27H28CLFN8O3 |
| Molecular Weight | 567.02 |
| Exact Mass | 566.195 |
| CAS # | 873837-23-1 |
| Related CAS # | BMS-599626;714971-09-2 |
| PubChem CID | 46930994 |
| Appearance | White to off-white solid powder |
| LogP | 4.421 |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 9 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 40 |
| Complexity | 828 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | CC1=C2C(=NC=NN2C=C1NC(=O)OC[C@@H]3COCCN3)NC4=CC5=C(C=C4)N(N=C5)CC6=CC(=CC=C6)F.Cl |
| 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 |
| 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 |
| Synonyms | BMS-599626; BMS599626; BMS 599626; AC 480; AC-480; AC480; AC480; AC 480 HCl; AC 480 hydrochloride; BMS599626; BMS-599626; BMS 599626; BMS599626 HCl; BMS599626 hydrochloride. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | BMS-599626 Hydrochloride prevents tumor cells from proliferating when HER1/HER2 signaling is present. With an IC50 of 0.3 and 0.22 μM, BMS-599626 Hydrochloride (0.03-8 μM; 1 hour) suppresses both receptor autophosphorylation and MAPK phosphorylation in Sal2 cells expressing CD8HER2 fusion protein [1]. With IC50 values ranging from 0.24 to 1 μM, BMS-599626 Hydrochloride suppresses the growth of tumor cell types that rely on HER1 and HER2 receptors while also completely eliminating these communication pathways. In GEO cells, BMS-599626 hydrochloride (IC50=0.75 μM) inhibits HER1 phosphorylation and stimulates it when treated with EGF. The EGF-dependent MAPK (0.8 μM) is also nearly completely inhibited, but AKT signaling is only somewhat inhibited. Multiple upstream activating signals for AKT may be reflected in the latter case. By amplification of the HER2 gene (0. 38 μM) and phosphorylation of AKT and MAPK (0. 35 μM), treatment of N87 cells with BMS-599626 hydrochloride suppresses high-level expression of HER2 [1]. This medicine (BMS-599626 HydroHClide) at the molecular level decreases the expression of pEGFR, pHER2, cyclin D and E, pRb, pAkt, pMAPK, pCDK1 and 2, CDK 6, and Ku70 proteins in HN-5 cells. In addition, BMS-599626 Hydrochloride can promote radiosensitivity, prolong the duration of γ-HA AX lesions to 24 hours following radiation, suppress cell proliferation, and cause an accumulation of cells in the G1 cell cycle phase [2]. |
| ln Vivo | The growth of Sal2 tumors is dose-dependently inhibited by BMS-599626 hydrochloride (60-240 mg/kg; po; daily for 14 days)[1]. Treatment with BMS-599626 Hydrochloride, administered once daily for 14 days, inhibits the growth of GEO xenograft tumors. A549 and L2987 are two examples of HER1-overexpressing non-small-cell lung cancers, while BT474 and N87 gastric tumors are two more HER2 amplified xenograft models in which BMS-599626 exhibits comparable anticancer activity in addition to its efficacy in the Sal2, GEO, and KPL4 models[1]. The radioresponse of HN5 tumors in vivo was enhanced by BMS-599626 Hydrochloride when administered both before and during irradiation[2]. |
| Animal Protocol |
Animal/Disease Models: Athymic female nude mice (nu/nu (nude) mice, Sal2 tumor model)[1] Doses: 60, 120, 240 mg/kg Route of Administration: Oral; daily for 14 days Experimental Results: Resulted in a dose-dependent inhibition of Sal2 tumor growth. |
| References |
[1]. 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. [2]. 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. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.41 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.41 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (4.41 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7636 mL | 8.8180 mL | 17.6361 mL | |
| 5 mM | 0.3527 mL | 1.7636 mL | 3.5272 mL | |
| 10 mM | 0.1764 mL | 0.8818 mL | 1.7636 mL |