AV-412 free base

AV-412 is a dual EGFR/ErbB2 kinase inhibitor with IC50 values of 43nM and 282nM, respectively [1].

In the H1650 and H1975 cell lines containing EGFR mutations, AV-412 inhibits EGFR autophosphorylation and the consequent activation of Akt and Erk at 0.1μM. In the H1781 cell line containing ErbB2 mutation, AV-412 also suppresses the phosphorylation of EGFR as well as ErbB2 and ErbB3. It decreases the phosphorylation of Akt and Erk [2].

AV-412 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. The H520 lung cancer is not sensitive to AV-412 due to the lack of EGFR and ErbB2 in it [2].

References:
[1] 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.
[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.

Antitumor activity of a dual epidermal growth factor receptor and ErbB2 kinase inhibitor MP-412 (AV-412) in mouse xenograft models.[Pubmed:19459856]

Cancer Sci. 2009 Aug;100(8):1526-31.

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. When its antitumor spectrum was further explored in several cancer types overexpressing EGFR or ErbB2, MP-412 showed potent activity in KPL-4 and DU145 xenografts, in which lapatinib was ineffective. MP-412 also inhibited tumor models in which conventional chemotherapies were less effective. These results suggest that MP-412 is a potent dual inhibitor with the potential for treating solid cancers that overexpress EGFR or ErbB2, including NSCLC cells harboring mutations resistant to the first generation of kinase inhibitors.

Pharmacological characterization of MP-412 (AV-412), a dual epidermal growth factor receptor and ErbB2 tyrosine kinase inhibitor.[Pubmed:17888033]

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

Epidermal growth factor receptor (EGFR) and ErbB2 are currently recognized as validated target molecules in cancer treatment strategies. 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.

AV-412 free base (MP-412 free base) 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.

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