Discovery of P11–2: A Potent First-in-Class MNK1-Targeting PROTAC Degrader for the Treatment of Cancer

MAPK-interacting kinases (MNKs) are the only known kinases that phosphorylate eIF4E at Ser209, playing a critical role in tumor progression. However, the current MNK inhibitors have been limited due to the deficiency of effectiveness. Herein, we reported the design of the first-in-class MNK1-targeting PROTACs based on the MNK1 inhibitor DS12881479. Among them, P11-2 exhibited robust antitumor activity against MV4-11 cells (IC50 = 45 nM) by efficiently degrading MNK1 (DC50 = 11.92 nM, Dmax > 96%) mediated by the ubiquitin-proteasome system. Notably, P11-2 does not degrade MNK2, which played an important role in maintaining normal function. Moreover, P11-2 significantly suppressed the phosphorylation of eIF4E (IC50 = 22.07 nM), induced apoptosis, and arrested the cell cycle at the G1 phase. In addition, P11-2 exhibited favorable PK profiles and robust antitumor effects in the xenograft model. These findings highlight the potential of P11-2 as a novel therapeutic strategy for targeting the degradation of MNK1.