Phenylglycine and phenylalanine derivatives as potent and selective (H)under-barDAC(1)over-cap (i)under-barnhibitors (SHI-1)

An HTS screening campaign identified a series of low molecular weight phenols that showed excellent selectivity (> 100-fold) for HDAC1/HDAC2 over other Class I and Class II HDACs. Evolution and optimization of this HTS hit series provided HDAC1-selective (SHI-1) compounds with excellent anti-proliferative activity and improved physical properties. Dose-dependent efficacy in a mouse HCT116 xenograft model was demonstrated with a phenylglycine SHI-1 analog. (C) 2008 Elsevier Ltd. All rights reserved.