Discovery of Novel Pyridine-Dihydropyrrolo[3,4- b ]Pyrrolidone Derivatives as Orally Active PIM Kinase Inhibitors for the Treatment of Acute Myeloid Leukemia
Yabing Xin, Nan Wang, Ziyao Xie, Yulu Li, Chihong Liu, Qichao Bao, Huidan Wu, Zihe Zhou, Ruichen Sun, Beibei Lu, Qidong You, Zhengyu Jiang, Mengchen LuAbstract
PIM kinases are promising therapeutic targets for acute myeloid leukemia (AML). Merging PIM447 with C28 via molecular hybridization, we successfully designed and synthesized a series of novel pyridine-dihydropyrrolo [3,4-b]pyrrolidone derivatives. Among them, compound 50 exhibited potent inhibitory activity against PIM-1/2/3 (IC50 = 6.71/15.14/10.10 nM, respectively) and significant antiproliferative activity against MV4-11 cells (IC50 = 0.21 μM). Mechanistic studies demonstrated that 50 dose-dependently inhibited substrate phosphorylation (e.g., BAD), thereby inducing PARP cleavage, apoptosis, and G2/M arrest. It possesses favorable drug-like properties and high oral bioavailability. Kinase profiling against 217 kinases showed good PIM selectivity. In an MV4-11 xenograft model, oral administration of 50 at 50 mg/kg once daily achieved 84.7% tumor growth inhibition without significant toxicity, and platelet toxicity was lower than C28. Overall, compound 50 is a potent, orally bioavailable PIM kinase inhibitor with a favorable safety profile that warrants further systematic evaluation in AML models with diverse genetic backgrounds.