AV-412 Tosylate

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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.

Price and Availability

AV-412 Tosylate , purity > 98%, is in stock. The same day shipping out after order is received.

Chemical Structure

Theoretical Analysis

MedKoo Cat#: 200944Name: AV-412 TosylateCAS#: 451493-31-5 (tosylate)Chemical Formula: C41H44ClFN6O7S2Exact Mass: Molecular Weight: 850.24Elemental Analysis: C, 57.84; H, 5.21; Cl, 4.16; F, 2.23; N, 9.87; O, 13.15; S, 7.53

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

Technical Data

Additional Information

Related:451493-31-5 (AV-412tosylate)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).    

References

1: Suzuki T, Fujii A, Ochi H, Nakamura H.Ubiquitination and downregulation of ErbB2 and estrogen receptor-alphaby 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 ErbB2kinase 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 epidermalgrowth factor receptor and ErbB2 tyrosine kinase inhibitor. Cancer Sci.2007 Dec;98(12):1977-84. Epub 2007 Sep 18. PubMed PMID: 17888033.