Hydroxamate-based HDAC inhibitors have promising anticanceractivitiesbut metabolic instability and poor pharmacokinetics leading to poorin vivo results. QSAR and PK studies of HDAC inhibitors showed thata ?-lactam core and a modified cap group, including halo, alkyl,and alkoxy groups with various carbon chain linkers, improved HDACinhibition and metabolic stability. The biological properties of the?-lactam HDAC inhibitors were evaluated; the compound designated 8fhad potent anticancer activity and high oral bioavailability. [ABSTRACT FROM AUTHOR]