AV-412
(Synonyms: MP412) 目录号 : GC35435
A dual inhibitor of EGFR and HER2
Cas No.:451493-31-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | Recombinant intracellular kinase domains of EGFR, EGFRL858R, EGFRT790M, EGFRL858R/T790M, and purified EGFR from A431 cell membranes are used. Kinase reactions are carried out in 8 mM MOPS (pH 7.0), 0.2 mM ethylenediaminetetraacetic acid (EDTA), 10 mM MnCl2, 10 mM Mg acetate, 0.1 mg/mL poly(Glu, Tyr) 4:1, [γ33P-ATP], and 5–10 mU of enzyme, except that 250 µM of the GGMEDIYFEFMGGKKK peptide substrate is used for EGFRT790M. Phosphorylation is initiated by the addition of ATP and is allowed to proceed for 40 min at room temperature. The reaction is stopped by the addition of 3% phosphoric acid, then aliquots of the reaction mixture are spotted onto a filtermat. After rinsing to remove peptides bound non-specifically, the filter is scintillation counted[1]. |
Cell experiment: | To test the effects of AV-412 on growth factor-dependent cell proliferation, A431 and A7r5 cells are cultured for 24 h at 37°C in the presence of 1 ng/mL epidermal growth factor and 50 ng/mL platelet-derived growth factor, respectively. The 3H-thymidine incorporation during this period is measured[1]. |
Animal experiment: | Mice: For studies examining the dosing schedule in relation to efficacy against TE-8 tumors, AV-412 is administered either once daily, every other day, or once per week for 2 weeks. Mice are killed 1 day after the final treatment, and the tumors are dissected and weighed. For evaluation of tumor phosphorylation, tumor-bearing mice are given a single administration of AV-412 and tumors are dissected 4 h later[1]. |
References: [1]. Suzuki T, et al. Pharmacological characterization of MP-412 (AV-412), a dual epidermal growth factor receptorand ErbB2 tyrosine kinase inhibitor. Cancer Sci. 2007 Dec;98(12):1977-84. | |
AV-412 is a dual inhibitor of EGFR and HER2 (IC50s = 1.4, 0.51, 0.79, 2.3, and 19 nM for the EGFR, EGFRL858R, EGFRT790M, EGFRL858R,T790M, and HER2 recombinant intracellular kinase domains, respectively).1 It is selective for EGFR and HER2 over IRK, MEK1, PKA, and PKC (IC50s = >10 μM) but also inhibits Abl, FLT1, and Src (IC50s = 41, 920, and 2,000 nM, respectively). AV-412 (10 and 30 μM) induces ubiquitination and degradation of HER2 in SK-BR-3 cells.2 It decreases levels of HER2 and estrogen receptor α (ERα) and increases levels of Hsp70 in MCF-7 cells when used at a concentration of 10 μM. AV-412 inhibits EGF-stimulated growth of A431 cells (IC50 = 0.1 μM).1 It reduces tumor growth in an A431 mouse xenograft model when administered at doses of 10 and 30 mg/kg and in a BT-474 mouse xenograft model at 30 mg/kg.
1.Suzuki, T., Fujii, A., Ohya, J., et al.Pharmacological characterization of MP-412 (AV-412), a dual epidermal growth factor receptor and ErbB2 tyrosine kinase inhibitorCancer Sci.98(12)1977-1984(2007) 2.Suzuki, T., Fujii, A., Ochi, H., et al.Ubiquitination and downregulation of ErbB2 and estrogen receptor-alpha by kinase inhibitor MP-412 in human breast cancer cellsJ. Cell. Biochem.112(9)2279-2286(2011)
| Cas No. | 451493-31-5 | SDF | |
| 别名 | MP412 | ||
| Canonical SMILES | O=S(C1=CC=C(C)C=C1)(O)=O.C=CC(NC2=CC3=C(NC4=CC=C(F)C(Cl)=C4)N=CN=C3C=C2C#CC(N5CCN(C)CC5)(C)C)=O.O=S(C6=CC=C(C)C=C6)(O)=O | ||
| 分子式 | C41H44ClFN6O7S2 | 分子量 | 851.41 |
| 溶解度 | DMSO: ≥ 28 mg/mL (32.89 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.1745 mL | 5.8726 mL | 11.7452 mL |
| 5 mM | 0.2349 mL | 1.1745 mL | 2.349 mL |
| 10 mM | 0.1175 mL | 0.5873 mL | 1.1745 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Pharmacological characterization of MP-412 (AV-412), a dual epidermal growth factor receptor and ErbB2 tyrosine kinase inhibitor
Cancer Sci 2007 Dec;98(12):1977-84.PMID:17888033DOI:10.1111/j.1349-7006.2007.00613.x.
Epidermal growth factor receptor (EGFR) and ErbB2 are currently recognized as validated target molecules in cancer treatment strategies. MP-412 (AV-412) is a potent dual inhibitor of EGFR and ErbB2 tyrosine kinases, including the mutant EGFR(L858R,T790M), which is clinically resistant to the EGFR-specific kinase inhibitors erlotinib and gefitinib. In an enzyme assay, MP-412 inhibited the EGFR variants and ErbB2 in the nanomolar range with over 100-fold selectivity compared with other kinases, apart from abl and flt-1, which were both moderately sensitive to the compound. In cells, MP-412 inhibited autophosphorylation of EGFR and ErbB2 with IC(50) of 43 and 282 nM, respectively. It also inhibited epidermal growth factor (EGF)-dependent cell proliferation with an IC(50) of 100 nM. Moreover, MP-412 abrogated EGFR signaling in the gefitinib-resistant H1975 cell line, which harbors a double mutation of L858R and T790M in EGFR. In animal studies using cancer xenograft models, MP-412 (30 mg/kg) demonstrated complete inhibition of tumor growth of the A431 and BT-474 cell lines, which overexpress EGFR and ErbB2, respectively. MP-412 suppressed autophosphorylation of EGFR and ErbB2 at the dose corresponding to its antitumor efficacy. When various dosing schedules were applied, MP-412 showed significant effects with daily and every-other-day schedules, but not with a once-weekly schedule, suggesting that frequent dosing is preferable for this compound. Furthermore, MP-412 showed a significant antitumor effect on the ErbB2-overexpressing breast cancer KPL-4 cell line, which is resistant to gefitinib. These studies indicate that MP-412 has potential as a therapeutic agent for the treatment of cancers expressing EGFR and ErbB2, especially those resistant to the first generation of small-molecule inhibitors.
Antitumor activity of a dual epidermal growth factor receptor and ErbB2 kinase inhibitor MP-412 (AV-412) in mouse xenograft models
Cancer Sci 2009 Aug;100(8):1526-31.PMID:19459856DOI:10.1111/j.1349-7006.2009.01197.x.
Although epidermal growth factor receptor (EGFR) kinase inhibitors are effective for the treatment of non-small cell lung cancer (NSCLC), the emergence of mutations resistant to these inhibitors, such as T790M, has become a clinical problem. Recently, ErbB2 mutations have also been identified in a small number of NSCLC patients. Therefore, novel therapies to overcome these mutations are desirable. We describe the antitumor activity of MP-412 (AV-412), a dual EGFR/ErbB2 kinase inhibitor, against three lung cancer models with EGFR and ErbB2 mutations and also against various human xenografts with overexpression of these receptors. MP-412 inhibited phosphorylation of EGFR and its downstream signaling in NCI-H1650 and NCI-H1975 cell lines, which harbor the E746-A750 deletion and L858R + T790M point mutations, respectively, in EGFR. MP-412 inhibited the growth of these cell lines in vitro and in vivo, whereas the precedent kinase inhibitors lapatinib, erlotinib, and gefitinib were ineffective against NCI-H1975 cells in vivo. Furthermore, MP-412 inhibited ErbB2 signaling in the NCI-H1781 cell line, which harbors the G776V,C insertion in ErbB2, and correlated with its antiproliferation activity. When its antitumor spectrum was further explored in several cancer types overexpressing EGFR or ErbB2, MP-412 showed potent activity in KPL-4 and DU145 xenografts, in which lapatinib was ineffective. MP-412 also inhibited tumor models in which conventional chemotherapies were less effective. These results suggest that MP-412 is a potent dual inhibitor with the potential for treating solid cancers that overexpress EGFR or ErbB2, including NSCLC cells harboring mutations resistant to the first generation of kinase inhibitors.
AACR-NCI-EORTC--21st International Symposium. Molecular targets and cancer therapeutics--Part 2
IDrugs 2010 Jan;13(1):10-2.PMID:20024839doi
The 21st international symposium of the American Association for Cancer Research (AACR), the NCI and the European Organization for Research and Treatment of Cancer (EORTC), held in Boston, included topics covering the development of therapeutics and molecular targets in the field of cancer research. This conference report highlights selected presentations on the development of novel drugs for cancer. Investigational drugs discussed include RO-506876 (F Hoffmann-La Roche Ltd), GDC-0980 (Genentech Inc), EMD-1214063 and EMD-1204831 (Merck Serono SA), AR-mTOR01 and AR-mTOR-26 (Array BioPharma Inc), GSK-2126458 (GlaxoSmithKline plc), EXEL-1415 and EXEL-2008 (Exelixis Inc), FP-1039 (FivePrime Therapeutics Inc), and AV-412 (AVEO Pharmaceuticals Inc).