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 <b>DS12881479</b>. Among them, <b>P11-2</b> exhibited robust antitumor activity against MV4-11 cells (IC₅₀ = 45 nM) by efficiently degrading MNK1 (DC₅₀ = 11.92 nM, <i>D</i>_max > 96%) mediated by the ubiquitin-proteasome system. Notably, P11-2 does not degrade MNK2, which played an important role in maintaining normal function. Moreover, <b>P11-2</b> significantly suppressed the phosphorylation of eIF4E (IC₅₀ = 22.07 nM), induced apoptosis, and arrested the cell cycle at the G1 phase. In addition, <b>P11-2</b> 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.