XY-27

XY-27 is a proteolysis-targeting chimera (PROTAC) designed to induce the degradation of MDM2 (Mouse Double Minute 2 homolog). It consists of an MDM2-binding ligand linked to a ligand for the von Hippel-Lindau (VHL) E3 ubiquitin ligase. By recruiting VHL to MDM2, XY-27 facilitates the ubiquitination and subsequent proteasomal degradation of MDM2. This mechanism is intended to overcome the negative feedback loop associated with traditional MDM2 inhibitors, where MDM2 protein levels often accumulate and limit therapeutic efficacy. In preclinical studies, XY-27 has demonstrated potent, TP53-dependent anti-leukemic activity in acute myeloid leukemia (AML) cell lines and primary patient samples, showing superior potency compared to small-molecule MDM2 inhibitors such as AMG232.