The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors.

Abstract Novel benzofuran-2-carboxylic acids, exemplified by 29 , 38 and 39 , have been discovered as potent Pim-1 inhibitors using fragment based screening followed by X-ray structure guided medicinal chemistry optimization. The compounds demonstrate potent inhibition against Pim-1 and Pim-2 in enzyme assays. Compound 29 has been tested in the Ambit 442 kinase panel and demonstrates good selectivity for the Pim kinase family. X-ray structures of the inhibitor/Pim-1 binding complex reveal important salt-bridge and hydrogen bond interactions mediated by the compound’s carboxylic acid and amino groups.