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.