AV-412 Tosylate - CAS 451493-31-5
Catalog number: B0084-454184
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
C41H44ClFN6O7S2
Molecular Weight:
851.41
COA:
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Targets:
EGFR
Description:
AV-412 is a dual EGFR/ErbB2 kinase inhibitor. It completely inhibits the tumor growth of both H1650 and H1975 xenografts in nude mice. It is proved that AV-412 suppresses tumor growth via the inhibition of EGFR. Besides that, AV-412 also shows antitumor effects against various tumor models expressing EGFR, ErbB2 or both receptors, such as breast cancer KPL-4, prostate cancer DU145 and lung cancer LC-376.
Purity:
>98%
Related CAS:
451492-95-8 (AV-412 free base)
Appearance:
Solid powder
Synonyms:
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); MP-412; MP 412; MP412; AV-412; AV 412; AV412; AV-412 tosylate
MSDS:
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InChIKey:
GTWJVFFZCKODEV-UHFFFAOYSA-N
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)
Canonical SMILES:
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
1.AACR-NCI-EORTC--21st International Symposium. Molecular targets and cancer therapeutics--Part 2.
Walker K;Padhiar M IDrugs. 2010 Jan;13(1):10-2.
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).
2.Ubiquitination and downregulation of ErbB2 and estrogen receptor-alpha by kinase inhibitor MP-412 in human breast cancer cells.
Suzuki T;Fujii A;Ochi H;Nakamura H J Cell Biochem. 2011 Sep;112(9):2279-86. doi: 10.1002/jcb.23147.
ErbB2 has been proven to be an important target for breast cancer therapy. MP-412 is a dual ErbB2 and epidermal growth factor receptor tyrosine kinase inhibitor belonging to an irreversible-type anilinoquinazoline derivative. We demonstrate herein that along with the kinase inhibition, MP-412 has the ability to induce ubiquitination, internalization, and degradation of ErbB2 in several human breast cancer cell lines at concentrations relatively higher than those required for kinase inhibition. Another irreversible inhibitor, CI-1033, showed similar activity, while the reversible compounds were ineffective, suggesting a crucial role of covalent bonding functionality in these effects. In MCF7 cells, MP-412 depleted not only ErbB2 but also estrogen receptor (ER)-α, and to some extent, affected Raf-1, while MP-412 activated Hsp70 expression. Moreover, we observed that MP-412 increased immunocomplexing of Hsp70 with ErbB2 and ER-α, with simultaneous induction of ubiquitination of these client proteins. Furthermore, in combination with proteasome inhibitor, MP-412 resulted in the noticeable accumulation of ErbB2 and ER-α in the detergent insoluble fraction of cell lysates. These results suggest that MP-412 acts as an inhibitor of Hsp90 function, whereas MP-412 did not bind directly to ATP-binding site of Hsp90, unlike geldanamycin.
3.Antitumor activity of a dual epidermal growth factor receptor and ErbB2 kinase inhibitor MP-412 (AV-412) in mouse xenograft models.
Suzuki T;Fujii A;Ohya J;Nakamura H;Fujita F;Koike M;Fujita M Cancer Sci. 2009 Aug;100(8):1526-31. doi: 10.1111/j.1349-7006.2009.01197.x. Epub 2009 May 13.
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.
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CAS 451493-31-5 AV-412 Tosylate

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