Ixazomib [MLN2238] (CAS: 1072833-77-2)

C₁₄H₁₉BCl₂N₂O₄

• Potent selective and reversible proteasome inhibitor (all proteolytic subunits).
• Targets the chymotrypsin-like β5 subunit of the constitutive 20S proteasome (IC₅₀=3.4nM). Cross-reacts and inhibits the trypsin-like β2 subunit (IC₅₀=3.5μM) and the caspase-like/peptidyl-glutamyl peptide-hydrolyzing (PGPH) β1 subunit (IC₅₀=0.03μM).
• Anticancer compound effective in cell-based assays, in xenografts and against multiple myeloma in vivo.
• In vitro, induces cell cycle arrest and apoptosis in human cancer cell lines including multiple myeloma.
• Biologically active form of the prodrug MLN9708 (Prod. No. AG-CR1-3671).
• Exhibits improved pharmacodynamics and antitumor activity compared to bortezomib (Prod. No. AG-CR1-3602) in various B cell lymphoma models, due to a greater tumor to blood ratio of proteasome inhibition that ultimately translates into improved tumor pharmacodynamic response and antitumor activity in several tumor xenograft models.

1. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer: E. Kupperman, et al.; Cancer Res. 70, 1970 (2010)
2. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells: D. Chauhan, et al.; Clin. Cancer Res. 17, 5311 (2011)
3. Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies: E.C. Lee, et al.; Clin. Cancer Res. 17, 7313 (2011)
4. Investigational agent MLN9708/2238 targets tumor-suppressor miR33b in MM cells: Z. Tian, et al.; Blood 120, 3958 (2012)
5. MLN2238, a proteasome inhibitor, induces caspase-dependent cell death, cell cycle arrest, and potentiates the cytotoxic activity of chemotherapy agents in rituximab-chemotherapy-sensitive or rituximab-chemotherapy-resistant B-cell lymphoma preclinical models: J.J. Gu, et al.; Anticancer Drugs 24, 1030 (2013)
6. Preclinical activity of the oral proteasome inhibitor MLN9708 in Myeloma bone disease: A. Garcia-Gomez, et al.; Clin. Cancer Res. 20, 1542 (2014)
7. The investigational agent MLN2238 induces apoptosis and is cytotoxic to CLL cells in vitro, as a single agent and in combination with other drugs: A. Paulus, et al.; Br. J. Haematol. 165, 78 (2014)
8. An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma: M. Offidani, et al.; Onco. Targets Ther. 7, 1793 (2014)
9. The investigational proteasome inhibitor ixazomib for the treatment of multiple myeloma: P.G. Richardson, et al.; Future Oncol. 11, 1153 (2015)
10. Comparison of antiproliferative and apoptotic effects of a novel proteasome inhibitor MLN2238 with bortezomib on K562 chronic myeloid leukemia cells: S. Engur, et al.; Immunopharmacol. Immunotoxicol. 38, 87 (2016)
11. Proteasomal Inhibition by Ixazomib Induces CHK1 and MYC-Dependent Cell Death in T-cell and Hodgkin Lymphoma: D. Ravi, et al.; Cancer Res. 76, 3319 (2016)
12. The potential of ixazomib, a second-generation proteasome inhibitor, in the treatment of multiple myeloma: J. Brayer & R. Baz; Ther. Adv. Hematol. 8, 209 (2017) (Review)