Hybridizing two PIM scaffolds into an oral AML lead with less platelet toxicity
- Merging the clinical PIM inhibitor PIM447 with a second PIM chemotype (C28) gave a pyridine-dihydropyrrolopyrrolidone series.
- The lead blocks all three PIM isoforms, cuts phosphorylation of substrates such as BAD, and drives apoptosis and G2/M arrest in an AML cell line.
- It was selective across a ~200-kinase panel, orally bioavailable, and suppressed tumor growth in an AML xenograft with lower platelet toxicity than C28.
💡 Points
Platelet toxicity is what has kept PIM inhibitors from being dosed hard enough, so a hybrid that improves that margin is the interesting part, not the potency. I'd want to see whether the gain comes from isoform balance or simply lower exposure in marrow. Without data in genetically varied AML models, I'd treat this as a promising scaffold rather than a settled lead.