標的誘導型合成 —標的酵素自身に阻害薬を合成させる創薬手法—

Abstract

Target-guided synthesis (TGS) is the method to allow target enzymes to synthesize their own inhibitors. The inhibitors identified by TGS are expected to show strong activity and high target-selectivity because they are synthesized by a specific reaction and/or in specific pockets of a target enzyme. Therefore, this approach would be useful for discovering novel selective enzyme inhibitors. Thus far, we found various enzyme inhibitors by means of TGS, i.e. (i) histone deacetylase (HDAC), human sirtuin (SIRT) and lysine-specific demethylase 1 (LSD1) inhibitors designed based on the enzymatic reaction mechanisms, (ii) LSD1 inactivators designed based on a direct target-drug delivery system and (iii) an HDAC8 inhibitor identified by in situ click chemistry utilizing an HDAC8/copper complex as a template. Here we present the design, synthesis, biological evaluation and inhibition mechanism analysis of these inhibitors.