Phenylglycine and phenylalanine derivatives as potent and selective HDAC1 inhibitors (SHI-1).

Phenylglycine and phenylalanine derivatives as potent and selective HDAC1 inhibitors (SHI-1).

Bioorganic & medicinal chemistry letters (2008-02-29)

Kevin J Wilson, David J Witter, Jonathan B Grimm, Phieng Siliphaivanh, Karin M Otte, Astrid M Kral, Judith C Fleming, Andreas Harsch, Julie E Hamill, Jonathan C Cruz, Melissa Chenard, Alexander A Szewczak, Richard E Middleton, Bethany L Hughes, William K Dahlberg, J Paul Secrist, Thomas A Miller

PMID18304810

摘要

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.