Discovery of YTB53, a Marine-Derived MNK-Active Anti-Acute Myeloid Leukemia Lead with Multi-Kinase Activity.

Acute myeloid leukemia (AML) remains a therapeutic challenge due to its aggressive nature and poor prognosis in relapsed/refractory cases. This study explores novel MNK (MAP kinase-interacting kinase) inhibitors derived from the marine natural product phorbazole C. Through systematic structure-activity relationship studies, compound 31 (YTB53) was identified as a potent MNK1/2-targeting compound with IC50 values of 0.037 and 0.009 μM, respectively. Kinase profiling further revealed that 31 also significantly inhibits PDGFRα, TRKB and FLT3, indicating that its antiproliferative activity in MV4-11 cells arises from multikinase engagement rather than selective MNK inhibition alone. Mechanistically, 31 induced cell cycle arrest, apoptosis, pyroptosis, and mitochondrial dysfunction. It also exhibited antiangiogenic effects and suppressed tumor growth in a xenograft model without overt toxicity. These findings support 31 as a promising multimechanistic lead for AML therapy, warranting further medicinal chemistry optimization to improve its pharmacokinetic properties and advance its development potential.