Ixazomib
First oral proteasome inhibitor for multiple myeloma, a boronic acid that reversibly inhibits the 20S proteasome beta5 subunit.
Chemical Identity
| Property | Value |
|---|---|
| Chemical Formula | C14H19BCl2N2O4 |
| Molecular Weight | 361.0 Da |
| CAS Number | 1072833-77-2 |
| Peptide Class | Boronic Acid (Modified Dipeptide) |
| Route | Oral (capsule) |
Structure
Ixazomib (Ninlaro) is a modified dipeptide boronic acid that is the first orally bioavailable proteasome inhibitor. It contains a citrulline-leucine backbone with a boronic acid warhead and two chlorine substituents on the phenyl ring. The molecule is administered as the citrate salt prodrug.
Mechanism of Action
Ixazomib reversibly inhibits the 20S proteasome beta5 subunit, blocking chymotrypsin-like proteolytic activity. This causes accumulation of ubiquitinated proteins, pro-apoptotic factors, and cell cycle inhibitors, leading to myeloma cell death. Oral bioavailability provides sustained proteasome inhibition.
Clinical Applications
- Multiple myeloma: With lenalidomide and dexamethasone after one prior therapy (Ninlaro)
- First-line myeloma: In combination regimens
- AL amyloidosis: Off-label combination therapy
- Waldenstrom macroglobulinemia: Investigational
Pharmacokinetics
- Half-life: 9.5 days (effective accumulation)
- Tmax: 1 hour
- Bioavailability: 58%
- Metabolism: CYP3A4 (primary), CYP1A2
- Route: Oral (days 1, 8, 15 of 28-day cycle)
Safety and Side Effects
Thrombocytopenia, diarrhea, constipation, nausea, peripheral neuropathy, peripheral edema, rash, and hepatotoxicity. Herpes zoster prophylaxis recommended.
References
- Moreau, P., et al. (2016). TOURMALINE-MM1: ixazomib for multiple myeloma. New England Journal of Medicine, 374, 1621-1634.
- Kumar, S.K., et al. (2014). Phase 1 study of ixazomib. Blood, 124, 1257-1265.
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