MLN-9708

MLN-9708, also known as ixazomib citrate, is a prodrug of Ixazomib (MMLN-2238). MLN-9708 is an orally bioavailable second generation proteasome inhibitor (PI) with potential antineoplastic activity. MLN-9708, after hydrolyzing to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity. MLN-9708, compared with bortezomib, has improved pharmacokinetics, pharmacodynamics, and antitumor activity in preclinical studies.

Product information

CAS Number: 1239908-20-3

Molecular Weight: 517.12

Formula: C20H23BCl2N2O9

Synonym:

MLN9708

MLN-9708

MLN 9708

ixazomib citrate

MMLN-2238-prodrug

MMLN 2238-prodrug

Ixazomib-prodrug

Ninlaro

MMLN2238-prodrug

Related CAS Number:

1201902-80-8 (hexatomic)

Chemical Name: 4-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid

Smiles: CC(C)C[C@H](NC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl)B1OC(CC(O)=O)(CC(O)=O)C(=O)O1

InChiKey: MBOMYENWWXQSNW-AWEZNQCLSA-N

InChi: InChI=1S/C20H23BCl2N2O9/c1-10(2)5-14(21-33-19(32)20(34-21,7-16(27)28)8-17(29)30)25-15(26)9-24-18(31)12-6-11(22)3-4-13(12)23/h3-4,6,10,14H,5,7-9H2,1-2H3,(H,24,31)(H,25,26)(H,27,28)(H,29,30)/t14-/m0/s1

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Solubility (25°C) DMSO: 100 mg/mL(193.37 mM). Water: Insoluble.

Shipping Condition: Shipped under ambien...

Storage Condition: Dry, dark and -20 ^oC...

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

MLN-9708, 0.20-3.20 µM inhibits the cell growth of both cell lines effectively in a time- and dose-dependent manner. MLN-9708 induces cell cycle arrest in MG-63 and Saos-2 cells. MLN-9708 induces apoptosis mainly through the caspases pathway and requires the activation of both caspase8 and caspase9. MLN-9708 treatment increases the levels of pro-apoptotic proteins and down regulates the anti-apoptotic proteins that control MOMP. MLN-9708 treatment induces the release of Cytc, Smac, OMI from mitochondria and decreases the protein levels of XIAP. MLN-9708 inhibits the invasion ability of MG-63 and Saos-2 cells and decreases both the expression and secretion levels of MMP2/9. MLN-9708; 12 nM shows inhibitory activity against C-L and T-L proteasome activities. Treatment of H929 and MM.1S MM cells with MLN-9708 triggers a marked increase in proteolytic cleavage of poly(ADP) ribose polymerase (PARP), a signature event during apoptosis. MLN-9708 induces cleavage of caspase-3, an upstream activator of PARP. MLN-9708 induces eIf2-α kinase activity and protein levels of Bip and CHOP/GADD153. MLN-9708 blocks BMSCs-induced MM cell proliferation, inhibits in vitro capillary tubule formation, and target NF-κB.

In Vivo:

MLN-9708, 11 mg/kg significantly inhibits MM tumor growth and prolongs survival in the human plasmacytoma MM.1S xenograft mouse model. The blood chemistry profiles of MLN-9708-treated mice show normal levels of creatinine, hemoglobin, and bilirubin. MLN-9708 dramatically increases the number of cleaved-caspase-3 positive cells of the xenograft mode.

References:

1. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from http://www.ncbi.nlm.nih.gov/books/NBK548002/ PubMed PMID: 31643334.
2. Tzogani K, Florez B, Markey G, Caleno M, Olimpieri OM, Melchiorri D, Hovgaard DJ, Sarac SB, Penttilä K, Lapveteläinen T, Salmonson T, Bergh J, Gisselbrecht C, Pignatti F. European Medicines Agency review of ixazomib (Ninlaro) for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. ESMO Open. 2019 Sep 8;4(5):e000570. doi: 10.1136/esmoopen-2019-000570. eCollection 2019. Review. PubMed PMID: 31555488; PubMed Central PMCID: PMC6735670.
3. Armoiry X, Spath HM, Clarke A, Connock M, Sutcliffe P, Dussart C. Comparison of health technology assessment for new medicines in France and England: anexample based on ixazomib for patients with relapsed or refractory multiple myeloma. J Mark Access Health Policy. 2019 Jul 30;7(1):1648971. doi: 10.1080/20016689.2019.1648971. eCollection 2019. Review. PubMed PMID: 31489149; PubMed Central PMCID: PMC6711145.
4. Smolewski P, Rydygier D. Ixazomib: an investigational drug for the treatment of lymphoproliferative disorders. Expert Opin Investig Drugs. 2019 May;28(5):421-433. doi: 10.1080/13543784.2019.1596258. Epub 2019 Apr 13. Review. PubMed PMID: 30907163.
5. Richardson PG, Zweegman S, O'Donnell EK, Laubach JP, Raje N, Voorhees P, Ferrari RH, Skacel T, Kumar SK, Lonial S. Ixazomib for the treatment of multiple myeloma. Expert Opin Pharmacother. 2018 Dec;19(17):1949-1968. doi: 10.1080/14656566.2018.1528229. Epub 2018 Nov 13. Review. PubMed PMID: 30422008.

Products are for research use only. Not for human use.