PARP-1, MDM2, and other mitoxantrone off-target proteins

This target profile represents a group of proteins, specifically Poly [ADP-ribose] polymerase 1 (PARP-1) and Mouse double minute 2 homolog (MDM2), which have been identified as significant off-targets or secondary targets of the anthracenedione drug mitoxantrone. PARP-1 is a nuclear enzyme essential for the detection and repair of DNA single-strand breaks; its inhibition can lead to genomic instability and is a key strategy in treating BRCA-deficient tumors (UniProt P09874). MDM2 is an E3 ubiquitin ligase that serves as the primary negative regulator of the p53 tumor suppressor, controlling cell cycle arrest and apoptosis (UniProt Q00987). While mitoxantrone is clinically utilized for its ability to inhibit Topoisomerase II and intercalate DNA, its interaction with PARP-1 and MDM2 contributes to its broad spectrum of cytotoxic and immunomodulatory activities (PMID: 22490530). These off-target effects are also implicated in the drug's notable safety profile, including dose-dependent cardiotoxicity and the risk of therapy-related secondary malignancies (FDA Label for Novantrone).

Other names

Poly [ADP-ribose] polymerase 1E3 ubiquitin-protein ligase Mdm2PARP1MDM2Mitoxantrone off-targets

Mitoxantrone acts primarily as a DNA intercalator and Topoisomerase II inhibitor, leading to DNA strand breaks (PubChem CID 4212). However, it also binds to and inhibits PARP-1, which interferes with the base excision repair pathway (PMID: 22490530). Additionally, mitoxantrone can modulate the MDM2-p53 axis, potentially influencing p53-mediated apoptotic signaling in cancer cells (PMID: 15507535).