Development of isoform-selective HDAC inhibitors is of highly medical importance,while remains as a significant challenge due to their highly structural similarity.Recently we studied the deacetylation catalytic mechanism in HDAC8 and observed the catalytic roles of metal ions(K+,which is 7(A)from the center Zn2+)[J.Am.Chem.Soc.,2010,132,9471.].And then guided by this mechanistic insights,we first in silico designed and then synthesized a novel HDAC2 selective inhibitor—QMC-16.The experimental studies show that the QMC-16 not only has a better isoform-selectivity(inhibiting HDAC1/2 not HDAC3)than a phase Ⅱ clinical inhibitor MS-275(inhibiting HDAC 1/2/3),but also demonstrates a distinct time-dependent selective-inhibition on HDAC2,leads to a 54-fold increase in inhibitory activity and about 20-fold isoform-selectivity against HDAC1.Finally,ab initio QM/MM MD simulations were further performed to explain the unique time-dependent selective-inhibition effect in HDAC2.