NES保有蛋白の核外移行阻害を標的とする新規医薬リード化合物の探索

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Recently, some proteins with nuclear export signal (NES), which is a characteristic sequence of amino acids, were shown to be exported from nucleus to cytoplasm with the aid of NES receptor protein CRM1. Mitogenactivated protein kinase kinase (MAPKK) and Rev were shown to be representative NES possessing proteins and play important roles in cytoplasm after export from nucleus. The former is concerned with proliferation of various tumor cells, the latter is required by replication of HIV 1 virus. In addition, inhibition of NES receptor, CRM1, led to suppress both proliferation of the tumor cells and replication of HIV1 virus potently. Up to date, leptomycin B (2) and callystatin A (3) have been only clarified to be inhibitors of CRM1. In this context, we constructed an assay system to search for another NES inhibitor by using the NLS GFP NES transformed yeast and disclosed a new NES inhibitor, vartrate (1), from Valerianae Radix through bioassayguided separation. By using the biotinylated probe derived from callystatin A (3), varflate (1) was presumed to inhibit export of the NES possessing proteins through binding to the Cys 529 in CRM1 in the same fashion as 2 and 3. Furtherriiore, the binding site of 1 to CRM1 was elucidated to be an epoxy moiety from the reactant of 1 and N acetylcysteine methyl ester