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Ref Type | Journal Article | ||||||||||||
PMID | (17888033) | ||||||||||||
Authors | Suzuki T, Fujii A, Ohya J, Amano Y, Kitano Y, Abe D, Nakamura H | ||||||||||||
Title | Pharmacological characterization of MP-412 (AV-412), a dual epidermal growth factor receptor and ErbB2 tyrosine kinase inhibitor. | ||||||||||||
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Abstract Text | 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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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AV-412 | MP-412 | EGFR Inhibitor (Pan) 61 EGFR Inhibitor 2nd gen 5 HER2 Inhibitor 41 | AV-412 binds and inhibits EGFR and ERBB2 (HER2), which may result in the inhibition of tumor growth and angiogenesis in EGFR/HER2-expressing tumors (PMID: 17888033, PMID: 19459856). |
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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