Rapid Affinity\nand Microsomal Stability Ranking of\nCrude Mixture Libraries of Histone Deacetylase Inhibitors

The science of drug discovery involves multiparameter\noptimization\nof molecular structures through iterative design–make–test\ncycles. For medicinal chemistry library synthesis, traditional workflows\ninvolve the isolation of each individual compound, gravimetric quantitation,\nand preparation of a standard concentration solution for biological\nassays. In this work, we explore ways to expedite this process by\ntesting unpurified library mixtures using a combination of mass spectrometry-based\nassays for affinity selection and microsomal metabolic stability.\nUtilizing this approach, microgram quantities of crude library mixtures\ncan be used to identify high affinity, metabolically stable library\nmembers for isolation and full characterization. This streamlined\napproach was demonstrated for the synthesis and evaluation of two\nlibraries of histone deacetylase inhibitors and was shown to generate\ndecision-making data in line with traditional workflows. The advantages\nof this paradigm include greatly reduced cycle time, reduced material\nrequirements, and concentration of resources on the most promising\ncompounds.