Sunday, August 30, 2015

Ixazomib | Proteoasme Inhibitor | Multiple Myeloma Treatment

MLN9708 [4-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid], a selective, orally bioavailable, second-generation proteoasme inhibitor that is under clinical investigation in multiple myeloma (MM). MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib (tradename: Velcade). Under physiological conditions, the stable citrate ester drug substance, ixazomib citrate (MLN9708), rapidly hydrolyzes to the biologically active boronic acid, MLN2238.

Ixazomib: 2D and 3D Structure

In studies where a solution of MLN9708 was added directly into rat, dog, or human plasma and immediately extracted and analyzed by high-performance liquid chromatography, only MLN2238 could be identified. MLN2238 is an N-capped dipeptidyl leucine boronic acid and preferentially bound to and inhibited the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 value of 3.4 nM (Ki = 0.93 nM). At higher concentrations, it also inhibited the caspase-like (β1) and trypsin-like (β2) proteolytic sites (IC50 of 31 and 3,500 nM, respectively) [1].

MLN9708 was selected from a large pool of boron-containing proteasome inhibitors based on a physicochemical profile that was distinct from bortezomib. MLN9708 has a shorter 20S proteasome dissociation half-life than bortezomib, which plays an important role in its improved tissue distribution. Direct comparison with bortezomib revealed that MLN9708 has an improved pharmacokinetic and pharmacodynamic profile and shows superior antitumor activity in both solid tumor and hematologic xenograft models, and shows antitumor activity when administered via multiple dosing routes and regimens [1].

In July 2015, Ixazomib was granted accelerated assessment by the Committee for Medicinal Products for Human Use (CHMP) of the EMA, a designation reserved for those medicines deemed to be of major public health interest and, in particular, therapeutic innovation.

In Nov 2015, Takeda Pharmaceutical Company Limited announced that the U.S. Food and Drug Administration (FDA) has approved Ninlaro (ixazomib) capsules, indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Ninlaro, the first and only oral proteasome inhibitor is a once-weekly pill.

The activity of Ixazomib is as follows:

Ki (20S Proteasome cell-free assay) = 0.93 nM

Common Name: Ixazomib
Synonyms: MLN-9708; MLN9708; MLN 9708; Ninlaro
IUPAC Name: 4-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid
CAS Number: 1201902-80-8; 1072833-77-2 (MLN2238)
Mechanism of Action: Proteoasme inhibitor
Indication: Various Cancers; Multiple Myeloma
Development Stage: Launched 2015
Company: Millennium Pharmaceuticals: The Takeda Oncology Company

1H NMR (Estimated) for Ixazomib


The most common adverse reactions occurring in greater than or equal to 20% of patients treated with Ixazomib were diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, rashes, vomiting and back pain. Moreover, it comes with warnings for hepatotoxixicty and embryo-fetal toxicity.

1. Kupperman, E.; et. al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res 201070(5), 1970-1980.