Alrizomadlin (APG-115): A Comprehensive Review of a Novel MDM2-p53 Inhibitor in Oncology

Executive Summary

Alrizomadlin (APG-115) is an investigational, orally bioavailable, small-molecule inhibitor of the Mouse Double Minute 2 (MDM2) E3 ubiquitin ligase. It represents a targeted therapeutic strategy designed to reactivate the tumor suppressor protein p53. By binding with high affinity and selectivity to MDM2, Alrizomadlin disrupts the critical MDM2-p53 protein-protein interaction, thereby preventing the degradation of p53 and restoring its potent tumor-suppressive functions, including the induction of cell cycle arrest and apoptosis. This mechanism is primarily effective in cancers that retain wild-type TP53 but exhibit functional p53 inactivation through overexpression or amplification of MDM2.

The clinical development of Alrizomadlin, led by Ascentage Pharma, has advanced to Phase 2 trials across a spectrum of solid and hematologic malignancies. Preclinical studies have validated its potent anti-proliferative activity and established a strong rationale for combination therapies. Emerging research has uncovered a multimodal mechanism of action that extends beyond classical apoptosis to include the induction of inflammatory pyroptotic cell death and significant modulation of the tumor microenvironment. This immunomodulatory activity provides a compelling biological basis for the observed clinical synergy with immune checkpoint inhibitors, particularly in overcoming resistance in cancers such as advanced melanoma.