Yasunori Kitano

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

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 EGFRL858R,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 IC50 of 43 and 282 nM, respectively. It also inhibited epidermal growth factor (EGF)‐dependent cell proliferation with an IC50 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. (Cancer Sci 2007; 98: 1977–1984)

Stereo- and enantioselective total synthesis of sarcophytol-A

Abstract The first total synthesis of sarcophytol-A, a biologically important marine cembranoid, was achieved in a highly stereo- and enantioselective manner.