AG 825

AG 825 is a selective inhibitor of ErbB2 with IC50 values of 0.15 and 19 μM for ErbB2 and ErbB1 respectively [1].

Receptor tyrosine-protein kinase erbB-2 is a member of the human epidermal growth factor receptor family and promotes cell proliferation.

AG 825 is a selective ErbB2 inhibitor. AG825 inhibited autophosphorylation of HER2, HER1-2 and HER1 with IC50 values of 0.15, 0.35 and 19 μM, respectively [1]. In non-small cell lung cancer (NSCLC) cell lines expressing high-p185neu, the HER-2/neu gene product, AG825 significantly increased the chemosensitivities. However, AG825 with high concentrations inhibited the drug-induced G2 arrest and the activation of phosphorylated p34cdc2 [2]. In androgen-independent prostate cancer (PCa) cell lines C4 and C4-2, AG825 was toxic in a dose- and time-dependent way and inhibited phosphoactivation of HER-2/neu and its down-regulation. Also, AG825 induced an imbalance between p38 mitogen-activated protein kinase activation and extracellular signal-regulated kinase 1/2, which then led to p38-dependent apoptosis [3].

References:
[1].  Osherov N, Gazit A, Gilon C, et al. Selective inhibition of the epidermal growth factor and HER2/neu receptors by tyrphostins. J Biol Chem, 1993, 268(15): 11134-11142.
[2].  Tsai CM, Levitzki A, Wu LH, et al. Enhancement of chemosensitivity by tyrphostin AG825 in high-p185(neu) expressing non-small cell lung cancer cells. Cancer Res, 1996, 56(5): 1068-1074.
[3].  Murillo H, Schmidt LJ, Tindall DJ. Tyrphostin AG825 triggers p38 mitogen-activated protein kinase-dependent apoptosis in androgen-independent prostate cancer cells C4 and C4-2. Cancer Res, 2001, 61(20): 7408-7412.

Apoptosis-modulating interaction of the neuregulin/erbB pathway with anthracyclines in regulating Bcl-xS and Bcl-xL in cardiomyocytes.[Pubmed:15733908]

J Mol Cell Cardiol. 2005 Mar;38(3):485-93.

During chemotherapy with anthracyclines, attenuated neuregulin signaling by the erbB2 receptor inactivating antibody Trastuzumab enhances the heart failure risk. We compared the effects of attenuated neuregulin/erbB signaling and of daunorubicin on splicing of the Bcl-x gene and on mitochondrial activation of apoptosis in cardiomyocytes. Attenuating erbB signals in cultured neonatal rat cardiomyocytes by the erbB2 antagonist tyrphostin AG825, by the erbB1/4 antagonist AG1478 or by antisense-induced lowering of erbB2 receptors resulted in an augmented Bcl-xS/Bcl-xL ratio, mitochondrial release of cytochrome c, activation of caspase 9 and caspase 3, and nucleosome-sized DNA fragmentation. A similar DNA fragmentation and caspase 3 activation was induced by TNF-alpha, but without Bcl-xS/Bcl-xL increase, cytochrome c release or caspase 9 activation. A BH4-domain containing HIV TAT fusion protein added to cardiomyocytes under attenuated erbB signaling lowered the enhanced Bcl-xS/Bcl-xL ratio, the cytochrome c release, the caspase 3 activation and the DNA fragmentation, while apoptosis was not modified by the fusion protein in TNF-alpha treated cardiomyocytes. Enhancement of Bcl-xS/Bcl-xL by reducing Bcl-xL via siRNA transfection mimicked the mitochondrial apoptotic activation due to erbB signal attenuation. Daunorubicin also caused Bcl-xS/Bcl-xL enhancement and mitochondrial apoptotic activation in cultured cardiomyocytes; this was attenuated by BH4-fusion protein or by neuregulin-1 and augmented by siRNA-mediated Bcl-xL lowering. We conclude that activation of mitochondrial apoptosis due to altered Bcl-x splicing contributes as a common mechanism of anthracyclines and erbB signal attenuation to the enhanced heart failure risk under this combination.

Degradation of HER2 receptor through hypericin-mediated photodynamic therapy.[Pubmed:19912559]

Photochem Photobiol. 2010 Jan-Feb;86(1):200-5.

Current treatment of breast cancer is often affected by resistance to therapeutics, for which the human epidermal growth factor receptor 2 (HER2) may be responsible. Here, we report for the first time the use of hypericin-mediated photodynamic therapy (HY-PDT) in combination with a selective HER2 inhibitor (AG 825) on SKBR-3, a HER2 overexpressing human breast adenocarcinoma cell line. The results demonstrate that HY-PDT is able to degrade HER2 with an impact on its signaling cascade. Combination with AG 825 resulted in increased apoptosis induction, total degradation of HER2 and inhibition of colony formation. Downregulation of HSP90, Mcl-1, Bcl-xL and upregulation of Bax was also observed. This knowledge provides the basis for the possible application of HY-PDT in preclinical and clinical models of breast cancer treatment.

Down-modulation of erbB2 activity is necessary but not enough in the differentiation of 3T3-L1 preadipocytes.[Pubmed:17990290]

J Cell Biochem. 2008 May 1;104(1):274-85.

The high incidence of obesity-related pathologies, led to the study of the mechanisms involved in preadipose cell proliferation and differentiation. Here, we demonstrate that modulation of erbB2, plays a fundamental role during proliferation and adipogenic induction of preadipocytes. Using 3T3-L1 cells as model, we demonstrate that EGF (10 nM, 5 min) in addition to stimulate receptor tyrosine phosphorylation of both erbB2 and EGFR, is able to induce the heterodimer erbB2-EGFR. We treated proliferating 3T3-L1 cells with two inhibitors, AG 825 (IC(50) 0.35 microM, 54 times more selective for erbB2 than for EGFR, IC(50) 19 microM), and AG 879 (IC(50) of 1 microM for erbB2 versus 500 microM for EGFR). We found that both inhibited the proliferation on a dose-dependent basis, reaching a 30% maximal inhibition at 100 microM (P < 0.001) for AG825, and a 20% maximal inhibition at 10 microM (P < 0.001) for AG 879. These results involve erbB2 in 3T3-L1 proliferation. When studying the differentiation process, we found that the action of MIX-Dexa immediately activates MEK, JNK and p38 kinases. We observed that PD98059 and SP600125 (MEK-ERK and JNK inhibitors, respectively) added 1 h prior to the MIX-Dexa induction produced a decrease in erbB2 expression after 6 h, which is even greater than the one produced by the inducers, MIX-Dexa. This work supports erbB2 as a key factor in 3T3-L1 adipogenesis, acting mostly and not only during the proliferative phase but also during the differentiation through modulation of both its expression and activity.

Tyrphostin AG825 triggers p38 mitogen-activated protein kinase-dependent apoptosis in androgen-independent prostate cancer cells C4 and C4-2.[Pubmed:11606371]

Cancer Res. 2001 Oct 15;61(20):7408-12.

Prostate cancer (PCa) progression is aided by abnormal autocrine growth factor loops. We screened for small cell-permeable inhibitors of receptor tyrosine kinases that could block their signaling and trigger cell death in PCa cell lines. We found that the human epidermal growth factor receptor (HER)-2/neu inhibitor tyrphostin AG825 is preferentially toxic to PCa cells that are phenotypically androgen independent. These effects were dose and time dependent in the human LNCaP, C4, and C4-2 cell line models of progression and correlated with the inhibition of HER-2/neu phosphoactivation and its down-regulation. In addition, we show that the inhibition of HER-2/neu signaling with AG825 triggers an imbalance between extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase activation, which leads to p38-dependent apoptosis. Inhibition of HER-1 with Compound 56 had no effect. These findings suggest that the androgen-independent C4 and C4-2 cells can be killed by selectively inhibiting their HER-2/neu signaling pathway and provide insights into the mechanism of action of AG825 in PCa cells.

Tyrphostins. 3. Structure-activity relationship studies of alpha-substituted benzylidenemalononitrile 5-S-aryltyrphostins.[Pubmed:7902440]

J Med Chem. 1993 Nov 12;36(23):3556-64.

In this study we describe an extension of our previous studies on cis-benzylidenemalononitrile tyrphostins. We have introduced S-aryl substituents in the 5 position (meta vis-a-vis the malononitrile moiety). We find that these compounds are potent blockers of EGFR kinase and its homolog HER-2 kinase. Interestingly, we find that certain S-aryltryphostins discriminate between EGFR and HER-2 kinase in favor of the HER-2 kinase domain by almost 2 orders of magnitude. When examined in intact cells it was found that these selective S-aryltrphostins are equipotent in inhibiting EGF dependent proliferation of NIH 3T3 harboring either the EGF receptor or the chimera EGF/neu (HER1-2). These findings suggest that the antiproliferative activity of these tyrphostins is mainly due to the inhibition of a mitogenic signaling element downstream to the growth receptor kinase.

Selective inhibition of the epidermal growth factor and HER2/neu receptors by tyrphostins.[Pubmed:8098709]

J Biol Chem. 1993 May 25;268(15):11134-42.

The HER2 (neu/erb-B2) proto-oncogene codes for a transmembrane receptor with tyrosine kinase activity and with high homology to the EGF receptor (HER1). The high incidence of HER2 overexpression in breast and ovary carcinomas prompted us to synthesize protein tyrosine kinase inhibitors (tyrphostins) which selectively inhibit the HER2 kinase activity. Two groups of tyrphostins were developed: one highly selective in inhibiting HER1 as opposed to HER2, the other highly selective in inhibiting HER2. Both the HER1 and the HER2 selective blockers were competitive with ATP binding. This suggests that even though the kinase domains of the respective receptors show an 80% degree of homology it is possible to design small molecules capable of discriminating between them. These results also show that the two kinases differ in their ATP binding sites. Mitogenic signaling induced by EGF in NIH3T3 cells overexpressing either HER1 or HER1-2 (possessing the HER2 kinase domain) was blocked identically by the agents that discriminate between the two in vitro. This paradox was further explored and elucidated. We propose that high intracellular ATP levels prevent inhibitor binding to the receptor. The antiproliferative action of the two distinct selective tyrphostins observed may result from the inhibition of a downstream element, presumably a tyrosine kinase, which mediates mitogenic signaling.

AG-825 (Tyrphostin AG-825) is a selective and ATP-competitive ErbB2 inhibitor which suppresses tyrosine phosphorylation, with an IC50 of 0.35 μM. AG-825 displays anti-cancer activity. AG825 significantly accelerates apoptosis of human neutrophils. AG-825 is a potential agent for overcoming Mn-induced neurotoxicity or AD development.

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