Milademetan

A small molecule inhibitor of MDM2

{{Drugbox | verifiedfields = changed | verifiedrevid = 477002123

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Milademetan chemical structure

| IUPAC_name = (2R)-2-[(4-[[4-(3-chloro-2-fluorophenyl)-5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]amino]phenyl)methyl]-1,3-dioxolane-2-carboxylic acid | tradename = | synonyms = DS-3032 | CAS_number = 1448867-41-1 | ATC_prefix = | ATC_suffix = | PubChem = 71587780 | ChemSpiderID = 32701364 | UNII = | KEGG = | ChEMBL = 3301614 | SMILES = C1CN(CCN1)C2=NC(=NC=C2C3=CC(=C(C=C3)N=C4C=CC(=NC4)C5=CC(=C(C=C5)F)Cl)C6COC(O6)C(=O)O)C | StdInChI = | StdInChIKey = }}

Milademetan is a small molecule inhibitor of the MDM2 protein, which is a negative regulator of the tumor suppressor protein p53. By inhibiting MDM2, milademetan aims to restore the function of p53, leading to the activation of p53-dependent pathways that can result in cell cycle arrest and apoptosis in cancer cells.

Mechanism of Action

Milademetan functions by binding to the MDM2 protein, thereby preventing its interaction with p53. Under normal circumstances, MDM2 binds to p53 and targets it for degradation via the ubiquitin-proteasome pathway. By inhibiting this interaction, milademetan stabilizes p53, allowing it to accumulate and activate its target genes involved in cell cycle regulation and apoptosis.

Clinical Development

Milademetan is currently under investigation in clinical trials for its potential use in treating various types of cancer, including liposarcoma, leukemia, and other solid tumors. The drug is being evaluated for its efficacy and safety in patients with tumors that have wild-type p53, as these are more likely to respond to MDM2 inhibition.

Pharmacokinetics

The pharmacokinetic profile of milademetan includes its absorption, distribution, metabolism, and excretion. It is designed to be orally bioavailable, allowing for convenient administration. The metabolism of milademetan is primarily hepatic, and it is excreted through both renal and fecal pathways.

Potential Side Effects

As with many cancer therapies, milademetan may have side effects. Commonly observed adverse effects in clinical trials include nausea, fatigue, and hematological toxicity such as neutropenia and thrombocytopenia. The safety profile is continuously being assessed in ongoing studies.

Research and Future Directions

Research on milademetan is focused on optimizing its therapeutic window and identifying biomarkers that predict response to treatment. Combination therapies with other anticancer agents are also being explored to enhance its efficacy and overcome resistance mechanisms.

Related Pages

• MDM2
• p53
• Cancer therapy
• Apoptosis
• Cell cycle arrest