MP-412 mesylate | AV-412 Tosylate | 451493-31-5 | 451492-95-8 | EGFR inhibitor

MedKoo Cat#: 200944 | Name: AV-412 Tosylate

Description:

WARNING: This product is for research use only, not for human or veterinary use.

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

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: 0.0000

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

Size	Price	Availability
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 650.00	Ready to ship
200mg	USD 950.00	Ready to ship
500mg	USD 1,650.00	Ready to ship
1g	USD 2,750.00	Ready to ship
2g	USD 3,950.00	Ready to ship

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Related CAS #

451492-95-8 (free base) 451493-31-5 (tosylate)

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

More Info

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).

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#SSC51121

QC Data

View QC data: current batch, Lot#SSC51121

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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

	Solvent	mg/mL	mM
Solubility
	DMSO	21.5	25.29
	DMSO:PBS (pH 7.2) (1:3)	0.3	0.29
	DMF	15.0	17.64
	Ethanol	0.3	0.29

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

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.

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:

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.

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.