title: Pharmacological characterization of MP-412 (AV-412), a dual epidermal growth factor receptor and ErbB2 tyrosine kinase inhibitor.
abstract: 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.
authors: Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. suzuki.tsuyoshi@mf.m-pharma.co.jp
authors: Tsuyoshi
authors: T
authors: Suzuki
authors: Akihiro
authors: A
authors: Fujii
authors: Junichi
authors: J
authors: Ohya
authors: Yusaku
authors: Y
authors: Amano
authors: Yasunori
authors: Y
authors: Kitano
authors: Daisuke
authors: D
authors: Abe
authors: Hideo
authors: H
authors: Nakamura
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D004938:Esophageal Neoplasms; D000077156:Gefitinib; D006801:Humans; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077156:Gefitinib; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; C525087:MP 412