Preclinical evaluation of a novel orally bioavailable MDM2 PROTAC, NW-8-461, in acute leukemia and myelofibrosis

Murine double minute 2 (MDM2) is a key negative regulator of the tumor suppressor p53 and is frequently overexpressed or amplified in p53-wild-type cancers, resulting in functional suppression of p53 signaling. Although small-molecule inhibitors that disrupt the MDM2-p53 interaction have demonstrated clinical activity, their efficacy is limited by on-target toxicity, incomplete pathway inhibition, and resistance driven by sustained MDM2 protein expression. Proteolysis-targeting chimeras (PROTACs) offer a novel therapeutic strategy by inducing selective and catalytic degradation of target proteins. Here, we describe NW-8-461, a potent MDM2-targeting PROTAC that induces efficient MDM2 degradation with a DC₅₀ <1 nM and robust activation of p53 signaling in RS4;11 leukemia cells. NW-8-461 exhibits markedly enhanced antiproliferative activity, demonstrating approximately 10-fold and 100-fold greater potency in cell viability assays compared with RG7388 and AMG232, respectively. Consistent with a p53-dependent mechanism, NW-8-461 selectively inhibits cell viability in myelofibrosis cell lines harboring wild-type p53 but not mutant p53. Notably, at 1 µM, NW-8-461 shows minimal or no degradation of key off-target proteins, including IKZF1, IKZF3, SALL4, GSPT1, and CK1alpha, indicating high target selectivity. In mice, NW-8-461 demonstrates favorable pharmacokinetics and oral bioavailability, achieving a plasma C_max of 9,660 ng/mL following a single oral dose of 50 mg/kg. In an orthotopic RS4;11-Luc leukemia model, treatment with NW-8-461 at 25 mg/kg for 16 days resulted in complete eradication of leukemia cells in 7/7 mice and significantly superior efficacy compared with the MDM2 inhibitor RG7388. These results establish NW-8-461 as a differentiated and highly selective MDM2 degrader with strong therapeutic potential for p53-wild-type malignancies.