NW-8-461

NW-8-461 is a potent, orally bioavailable proteolysis-targeting chimera (PROTAC) designed to induce the selective and catalytic degradation of Murine double minute 2 (MDM2). MDM2 is a critical negative regulator of the tumor suppressor p53, and its overexpression in p53-wild-type cancers leads to the functional suppression of p53 signaling. By inducing efficient MDM2 degradation (DC₅₀ < 1 nM), NW-8-461 reactivates the p53 pathway, demonstrating robust antiproliferative activity. Preclinical evaluations indicate that NW-8-461 is significantly more potent than traditional MDM2 inhibitors like RG7388 (idasanutlin) and AMG232 (siremadlin), with high selectivity and favorable pharmacokinetic properties. It has shown significant therapeutic potential in models of acute leukemia and myelofibrosis, including the complete eradication of leukemia cells in orthotopic mouse models.