ROTACMNK1degrader-1 is a selective MNK1 PROTAC degrader with a DC50 of 11.92 nM and a Dmax greater than 96% in MV4-11 cells. It significantly reduces p-eIF4E levels with an IC50 of 22.07 nM, induces apoptosis, and causes cell cycle arrest at the G1 phase. This compound exhibits potent antitumor activity, demonstrating strong anti-leukemic effects in MV4-11 xenograft mouse models with acceptable drug safety.

MNK1:11.92 nM(DC50)

PROTAC MNK1 degrader-1 (Compound P11-2) significantly enhances antiproliferative activity across four cancer cell lines (MV4-11, MM.1S, MOLM-13, and MDA-MB-231) at concentrations of 0.001-10 μM over 24 hours, with IC 50 values of 0.045, 0.24, 0.61, and 2.06 μM, respectively. At 300 nM for 1-24 hours, it induces MNK1 degradation in MV4-11 cells through a CRBN and proteasome-dependent mechanism, with a half-life (t 1/2) of 3.64 hours. Using 10-1000 nM over 24 hours, it selectively degrades MNK1 in MV4-11 cells, lowering levels of the downstream factor p-eIF4E with an IC 50 of 22.07 nM, thus effectively inhibiting tumor cell proliferation. PROTAC MNK1 degrader-1 demonstrates excellent binding affinity to the active sites of CRBN and MNK1, with its linker forming a hydrogen bond with H353. At 30-300 nM over 24 hours, it induces apoptosis in MV4-11 cells in a dose-dependent manner, particularly late apoptosis, and arrests the cell cycle at the G1 phase.

PROTAC MNK1 degrader-1 (Compound P11-2), administered intraperitoneally at 20 mg/kg daily for 16 days, significantly inhibits tumor growth in the MV4-11 xenograft mouse model by degrading MNK1 and further reduces p-eIF4E levels. At a dosage of 100 mg/kg administered intraperitoneally once daily for 14 days, it demonstrates acceptable drug safety with no evident toxicity to other major organs.