KCS

Proviral Integration Moloney murine leukemia virus (PIM) kinase, which is involved in the regulation of cellular processes such as survival, proliferation, cell cycle regulation, is overexpressed in hematological and solid cancers. It is a serine/threonine kinase with three homologous isomers of PIM-1, PIM-2, and PIM-3. PIM-1 kinase characteristically has a proline residue (Pro123) in the hinge region of the ATP binding site, and show high selectivity over other kinase inhibitors. In this study, using an indolin-2-one scaffold a series of novel compounds were designed and synthesized for PIM kinase inhibitor. Multiple substituents were introduced to the scaffold to make effective interaction not only with the carboxyl groups of Asp128 and Glu121, but also with the amino group of Lys67 of PIM-1 kinase. As a result of structure-activity relationship (SAR) study, the most potent inhibitor yielded IC₅₀ values of 5.6 nM and 6.9 nM for PIM-1 and PIM-3, respectively.