Discovery of a Potent Class I Selective Ketone Histone Deacetylase Inhibitor with Antitumor Activity in Vivo and Optimized Pharmacokinetic Properties

摘要

The optimization of a potent, class I selective ketone HDAC inhibitor is shown. It possesses optimized pharmacokinetic properties in preclinical species, has a clean off-target profile, and is negative in a microbial mutagenicity (Ames) test. In a mouse xenograft model it shows efficacy comparable to that of vorinostat at a 10-fold reduced dose.