ixazomib   Click here for help

GtoPdb Ligand ID: 8450

Synonyms: MLN-2238 | MLN2238 | Ninlaro®
Approved drug PDB Ligand
ixazomib is an approved drug (FDA (2015), EMA (2016))
Compound class: Synthetic organic
Comment: Ixazomib is the first approved oral proteasome inhibitor. Ixazomib reversibly inhibits 20S proteasome activity. Like bortezomib, ixazomib primarily inhibits the chymotrypsin-like (β5) proteolytic site within the 20S proteasome, but its pharmacokinetics, pharmacodynamics, and antitumor activity are superior to those of bortezomib [3].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 4
Rotatable bonds 9
Topological polar surface area 98.66
Molecular weight 360.08
XLogP 2.7
No. Lipinski's rules broken 0
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Canonical SMILES OB(C(NC(=O)CNC(=O)c1cc(Cl)ccc1Cl)CC(C)C)O
Isomeric SMILES OB([C@@H](NC(=O)CNC(=O)c1cc(Cl)ccc1Cl)CC(C)C)O
InChI InChI=1S/C14H19BCl2N2O4/c1-8(2)5-12(15(22)23)19-13(20)7-18-14(21)10-6-9(16)3-4-11(10)17/h3-4,6,8,12,22-23H,5,7H2,1-2H3,(H,18,21)(H,19,20)/t12-/m0/s1
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Summary of Clinical Use Click here for help
Ixazomib is being evaluated in several Phase 3 clinical trials for MM [4], and a single Phase 3 trial for relapsed/refractory systemic light chain amyloidosis. Phase 1 and II trials for other hematological cancers and solid tumours [3] such as bladder cancer and renal cell carcinoma (RCC) are ongoing.
Both the European EMA and US FDA have formally recognised the relevance of this drug as a potential therapy for treating serious or life-threatening conditions, in particular systemic light-chain amyloidosis (AL amyloidosis), a condition for which there is currently no approved treatment. The EMA have granted ixazomib orphan drug status and the FDA have granted breakthrough therapy designation for AL amyloidosis.
Full US FDA marketing approval was granted in November 2015, for ixazomib to be used in combination with lenalidomide and dexamethasone to treat patients with MM who have received at least one prior therapy.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Ixazomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome. Inhibitors of proteasome activity are antiproliferative and pro-apoptotic in nature. Proteasome inhibition leads to an increase in intracellular pro-apoptotic proteins, which promote cell-cycle arrest and cell-death [1]. Proteasome activity is reviewed in [2].
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