新規オキサゾロン系PIM-1キナーゼ阻害剤の構造誘導設計と評価、および有望ながん治療活性

PIM-1 kinase is a crucial modulator of cellular processes, including proliferation, survival and programmed cell death, positioning it as a compelling target for anticancer therapies. Using a structure-guided drug design strategy, we have designed novel oxazolone derivatives as potential PIM-1 inhibitors. Out of 42 designed oxazolone derivatives, molecular docking identified 30 candidates with favorable binding profiles. In this study, synthetic oxazolone derivatives (O20, O23 and O29) were evaluated for their inhibitory potential against PIM-1 through biochemical and biophysical approaches. Enzyme inhibition assays demonstrated consistent low-micromolar inhibition of PIM-1 with, 13.88 ± 1.8 µM for O20, 12.11 ± 2.5 µM for O23 and 15.04 ± 2.9 µM for O29. Fluorescence quenching confirmed potent ligand-protein interactions, with binding constants (Kₐ) in the order of 10⁵-10⁶ M^-1. ITC measurements further validated these findings, revealing favorable binding enthalpy (ΔH = -5.3 × 10⁵ kcal/mol for O29) and entropy-driven stabilization. Additionally, a cell proliferation assay was performed on a human prostate cancer cell line using compound O29, which showed promising anticancer potential with an IC₅₀ of 8.46 µM. Collectively, these results indicate that O29 is the most promising candidate among the tested derivatives, offering high-affinity binding and efficient kinase inhibition. These findings suggest the therapeutic potential of oxazolone-based scaffolds as lead compounds for the development of potent PIM-1 inhibitors in prostate cancer treatment.