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

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.

Fragment based screening using Surface Plasmon Resonance (SPR) followed by Pim-1 biochemical assay identified hit 10. A X-ray structure of the bound complex of 10 to the Pim-1 protein revealed that 10 binds in the ATP binding site with the 5-bromo group sitting in the hydrophobic pocket near the hinge region. Guided by the X-ray structures, a potent Pim-1 inhibitor 38 was identified by adding an aminocyclohexaylamino group at the 7-position of the benzofuran core. X-ray structure of the bound complex of 38 indicated that the terminal amino group forms salt-bridge interacts with D128 and E171 of the ribose binding site.Figure optionsDownload as PowerPoint slide