Potent Histone Deacetylase Inhibitors Derived from 4‑(Aminomethyl)‑<i>N</i>‑hydroxybenzamide with High Selectivity for the HDAC6 Isoform

A screen for HDAC6 inhibitors identified acyl derivatives of 4-(aminomethyl)-<i>N</i>-hydroxybenzamide as potent leads with unexpected selectivity over the other subtypes. We designed and synthesized constrained heterocyclic analogues such as tetrahydroisoquinolines that show further enhanced HDAC6 selectivity and inhibitory activity in cellular assays. Selectivity may be attributed to the benzylic spacer more effectively accessing the wider channel of HDAC6 compared to other HDAC subtypes as well as hydrophobic capping groups interacting with the protein surface near the rim of the active site

Discovery of a Potent and Orally Bioavailable Benzolactam-Derived Inhibitor of Polo-Like Kinase 1 (MLN0905)

This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (<b>12c</b>, MLN0905). In vivo pharmacokinetic–pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of <b>12c</b> to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model