Scaffold Hopping-Guided Design of Novel PIM-1 Inhibitors with Anticancer Activities

PIM kinases, as members of the serine/threonine kinase family, regulate key cellular processes such as proliferation, apoptosis, and metabolism by phosphorylating multiple substrates, making them important therapeutic targets for cancer treatment. In this study, we reported a series of structurally novel PIM-1 kinase inhibitors based on a scaffold-hopping strategy. After multiple rounds of structural optimization, the highly active compound <b>C2</b> was obtained, exhibiting an IC₅₀ of 33.02 ± 1.31 nM against PIM-1 kinase. Molecular docking results revealed that compound <b>C2</b> stably bound to the hydrophobic cavity of the PIM-1 protein and formed hydrogen bond interactions with polar residues in the hinge region, thereby effectively inhibiting kinase activity. In vitro antitumor assessment demonstrated significant proliferation inhibition of the hematological tumor cell line MM.1S (IC₅₀ = 1.87 μM), comparable to the positive control <b>SGI-1776</b> (IC₅₀ = 1.71 μM). In addition, compound <b>C2</b> possessed favorable drug-like properties and excellent stability in simulated gastrointestinal fluids and rat plasma. This study provides promising lead compounds for the development of novel PIM-1-targeted anticancer drugs, which can be further optimized.