AV-412 Tosylate
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MedKoo CAT#: 200944

CAS#: 451493-31-5 (tosylate)

Description: AV-412, also known as MP-412, is a second-generation, orally bioavailable dual kinase inhibitor with potential antineoplastic activity. EGFR/HER2 inhibitor AV-412 binds to and inhibits the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2), which may result in the inhibition of tumor growth and angiogenesis, and tumor regression in EGFR/HER2-expressing tumors. This agent may be active against EGFR/HER2-expressing tumor cells that are resistant to first-generation kinase inhibitors. EGFR and HER2 are receptor tyrosine kinases that play major roles in tumor cell proliferation and tumor vascularization.


Chemical Structure

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AV-412 Tosylate
CAS# 451493-31-5 (tosylate)

Theoretical Analysis

MedKoo Cat#: 200944
Name: AV-412 Tosylate
CAS#: 451493-31-5 (tosylate)
Chemical Formula: C41H44ClFN6O7S2
Exact Mass:
Molecular Weight: 850.24
Elemental Analysis: C, 57.84; H, 5.21; Cl, 4.16; F, 2.23; N, 9.87; O, 13.15; S, 7.53

Price and Availability

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100.0mg USD 650.0 Same Day
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500.0mg USD 1650.0 Same Day
1.0g USD 2750.0 Same Day
2.0g USD 3950.0 Same Day
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Related CAS #: 451492-95-8 (AV-412 free base)  

Synonym: MP-412; MP 412; MP412; AV-412; AV 412; AV412; AV-412 tosylate

IUPAC/Chemical Name: N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)quinazolin-6-yl)acrylamide bis(4-methylbenzenesulfonate)

InChi Key: GTWJVFFZCKODEV-UHFFFAOYSA-N

InChi Code: InChI=1S/C27H28ClFN6O.2C7H8O3S/c1-5-25(36)33-23-16-20-24(30-17-31-26(20)32-19-6-7-22(29)21(28)15-19)14-18(23)8-9-27(2,3)35-12-10-34(4)11-13-35;2*1-6-2-4-7(5-3-6)11(8,9)10/h5-7,14-17H,1,10-13H2,2-4H3,(H,33,36)(H,30,31,32);2*2-5H,1H3,(H,8,9,10)

SMILES Code: CC1=CC=C(C=C1)S(=O)(=O)O.CC1=CC=C(C=C1)S(=O)(=O)O.CC(C)(C#CC1=CC2=C(C=C1NC(=O)C=C)C(=NC=N2)NC3=CC(=C(C=C3)F)Cl)N4CCN(CC4)C

Appearance: Solid powder

Purity: >98%

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 in water

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: AV-412 (MP412) is an EGFR inhibitor with IC50s of 0.75, 0.5, 0.79, 2.3, 19 nM for EGFR, EGFRL858R, EGFRT790M, EGFRL858R/T790M and ErbB2, respectively.
In vitro activity: This study examined first the ability of MP-412 to inhibit phosphorylation signaling of ErbB2 in human breast cancer cell line T-47D. In western blotting, MP-412 showed complete inhibition of ErbB2 autophosphorylation as well as the consequent activation of Akt and Erk at 1 µM for only 1 h while both DMAG and PS-341 did not affect ErbB2 phosphorylation within this short period of time (Fig. 1A). This study also observed the ubiquitination and downregulation of ErbB2 by MP-412 in another cell line MCF7 (data not shown). These results indicated that MP-412 has the ability to induce ubiquitination and downregulation of ErbB2 at concentrations relatively higher than those required for kinase inhibition. Reference: J Cell Biochem. 2011 Sep;112(9):2279-86. https://onlinelibrary-wiley-com.libproxy.lib.unc.edu/doi/10.1002/jcb.23147
In vivo activity: This study next examined the antitumor effects of four TKI (MP-412, lapatinib, erlotinib, and gefitinib) in H1650 and H1975 xenografts in nude mice. Similar to the results of the in vitro assays, MP-412 completely inhibited the tumor growth of both H1650 and H1975 xenografts (Fig. 2). In contrast, lapatinib, erlotinib, and gefitinib showed no effects on H1975 xenografts, even at their MTD, despite the fact that they significantly inhibited the tumor growth of H1650 xenografts (Fig. 2). These results indicate that MP-412 is a potent inhibitor of tumor growth in lung cancer models with T790M mutation resistant to erlotinib, gefitinib, and lapatinib. Reference: Cancer Sci. 2009 Aug;100(8):1526-31. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1349-7006.2009.01197.x

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 21.5 25.29
DMSO:PBS (pH 7.2) (1:3) 0.25 0.29
DMF 15.0 17.64
Ethanol 0.25 0.29

Preparing Stock Solutions

The following data is based on the product molecular weight 850.24 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.

Recalculate based on batch purity %
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. Suzuki T, Fujii A, Ochi H, Nakamura H. Ubiquitination and downregulation of ErbB2 and estrogen receptor-alpha by kinase inhibitor MP-412 in human breast cancer cells. J Cell Biochem. 2011 Sep;112(9):2279-86. doi: 10.1002/jcb.23147. PMID: 21503962. 2. Suzuki T, Fujii A, Ohya J, Nakamura H, Fujita F, Koike M, Fujita M. 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. doi: 10.1111/j.1349-7006.2009.01197.x. Epub 2009 May 13. PMID: 19459856. 3. Suzuki T, Fujii A, Ohya J, Amano Y, Kitano Y, Abe D, Nakamura H. 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. doi: 10.1111/j.1349-7006.2007.00613.x. Epub 2007 Sep 18. PMID: 17888033.
In vitro protocol: 1. Suzuki T, Fujii A, Ochi H, Nakamura H. Ubiquitination and downregulation of ErbB2 and estrogen receptor-alpha by kinase inhibitor MP-412 in human breast cancer cells. J Cell Biochem. 2011 Sep;112(9):2279-86. doi: 10.1002/jcb.23147. PMID: 21503962. 2. Suzuki T, Fujii A, Ohya J, Nakamura H, Fujita F, Koike M, Fujita M. 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. doi: 10.1111/j.1349-7006.2009.01197.x. Epub 2009 May 13. PMID: 19459856.
In vivo protocol: 1. Suzuki T, Fujii A, Ohya J, Nakamura H, Fujita F, Koike M, Fujita M. 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. doi: 10.1111/j.1349-7006.2009.01197.x. Epub 2009 May 13. PMID: 19459856. 2. Suzuki T, Fujii A, Ohya J, Amano Y, Kitano Y, Abe D, Nakamura H. 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. doi: 10.1111/j.1349-7006.2007.00613.x. Epub 2007 Sep 18. PMID: 17888033.

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1: Suzuki T, Fujii A, Ochi H, Nakamura H. Ubiquitination and downregulation of ErbB2 and estrogen receptor-alpha by kinase inhibitor MP-412 in human breast cancer cells. J Cell Biochem. 2011 Sep;112(9):2279-86. doi: 10.1002/jcb.23147. PubMed PMID: 21503962.

2: Suzuki T, Fujii A, Ohya J, Nakamura H, Fujita F, Koike M, Fujita M. 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. Epub 2009 May 13. PubMed PMID: 19459856.

3: Suzuki T, Fujii A, Ohya J, Amano Y, Kitano Y, Abe D, Nakamura H. 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. Epub 2007 Sep 18. PubMed PMID: 17888033.



Additional Information

Related:
451493-31-5 (AV-412 tosylate)
451492-95-8 (AV-412 free base).

  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. (source: Cancer Sci. 2007 Dec;98(12):1977-84).