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Details

Stereochemistry ABSOLUTE
Molecular Formula C14H19BCl2N2O4
Molecular Weight 361.029
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of IXAZOMIB

SMILES

CC(C)C[C@H](NC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl)B(O)O

InChI

InChIKey=MXAYKZJJDUDWDS-LBPRGKRZSA-N
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

HIDE SMILES / InChI

Molecular Formula C14H19BCl2N2O4
Molecular Weight 361.029
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

Ixazomib (trade name Ninlaro) is a drug for the treatment of multiple myeloma in adults after at least one prior therapy, in combination with lenalidomide and dexamethasone. It is taken by mouth in form of capsules. Common side effects include diarrhea, constipation and low platelet count. Like the older bortezomib (which can only be given by injection), it acts as a proteasome inhibitor, has orphan drug status in the US and Europe. At therapeutic concentrations, ixazomib selectively and reversibly inhibits the protein proteasome subunit beta type-5 (PSMB5) with a dissociation half-life of 18 minutes. This mechanism is the same as of bortezomib, which has a much longer dissociation half-life of 110 minutes; the related drug carfilzomib, by contrast, blocks PSMB5 irreversibly. Proteasome subunits beta type-1 and type-2 are only inhibited at high concentrations reached in cell culture models. PSMB5 is part of the 20S proteasome complex and has enzymatic activity similar to chymotrypsin. It induces apoptosis, a type of programmed cell death, in various cancer cell lines. A synergistic effect of ixazomib and lenalidomide has been found in a large number of myeloma cell lines. The medication is taken orally as a prodrug, ixazomib citrate, which is a boronic ester; this ester rapidly hydrolyzes under physiological conditions to its biologically active form, ixazomib, a boronic acid. Absolute bioavailability is 58%, and highest blood plasma concentrations of ixazomib are reached after one hour. Plasma protein binding is 99%.

CNS Activity

Approval Year

PubMed

PubMed

TitleDatePubMed
Intracellular protein degradation: from a vague idea, through the lysosome and the ubiquitin-proteasome system, and onto human diseases and drug targeting (Nobel lecture).
2005 Sep 19
Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma.
2007 Apr
Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer.
2010 Mar 1
An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma.
2014
Ixazomib for the treatment of multiple myeloma.
2015
The investigational proteasome inhibitor ixazomib for the treatment of multiple myeloma.
2015
Therapeutic landscape of carfilzomib and other modulators of the ubiquitin-proteasome pathway.
2015 Mar 1
Patents

Sample Use Guides

In Vivo Use Guide
Recommended starting dose of 4 mg taken orally on Days 1, 8, and 15 of a 28-day cycle.
Route of Administration: Oral
In Vitro Use Guide
In a cell viability assay, MM.1S {Dexamethasone-(Dex) sensitive}, MM.1R (Dex-resistant), RPMI-8226, OPM1, OPM2, H929 and INA-6 (IL-6-dependent) human multiple myeloma cell lines were treated with various concentrations of ixazomib (6.25, 12.5, 25, 50 nM) for 48h. The anti-myeloma activity of the drug was observed in MM cell lines sensitive and resistant to conventional therapies, as well as representing distinct cytogenetic profiles.
Substance Class Chemical
Created
by admin
on Mon Oct 21 20:56:38 UTC 2019
Edited
by admin
on Mon Oct 21 20:56:38 UTC 2019
Record UNII
71050168A2
Record Status Validated (UNII)
Record Version
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Name Type Language
IXAZOMIB
DASH   INN   USAN   WHO-DD  
USAN   INN  
Official Name English
MLN2238
Code English
IXAZOMIB [USAN]
Common Name English
IXAZOMIB [WHO-DD]
Common Name English
MLN-9708 FREE BASE
Code English
MLN-2238
Code English
((1R)-1-((2,5-DICHLOROBENZAMIDO)ACETAMIDO)-3-METHYLBUTYL)BORONIC ACID
Systematic Name English
IXAZOMIB [INN]
Common Name English
BORONIC ACID, B-((1R)-1-((2-((2,5-DICHLOROBENZOYL)AMINO)ACETYL)AMINO)-3-METHYLBUTYL)-
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C2160
Created by admin on Mon Oct 21 20:56:39 UTC 2019 , Edited by admin on Mon Oct 21 20:56:39 UTC 2019
WHO-ATC L01XX50
Created by admin on Mon Oct 21 20:56:39 UTC 2019 , Edited by admin on Mon Oct 21 20:56:39 UTC 2019
NDF-RT N0000175604
Created by admin on Mon Oct 21 20:56:39 UTC 2019 , Edited by admin on Mon Oct 21 20:56:39 UTC 2019
EU-Orphan Drug EU/3/12/1060
Created by admin on Mon Oct 21 20:56:39 UTC 2019 , Edited by admin on Mon Oct 21 20:56:39 UTC 2019
Code System Code Type Description
PUBCHEM
25183872
Created by admin on Mon Oct 21 20:56:39 UTC 2019 , Edited by admin on Mon Oct 21 20:56:39 UTC 2019
PRIMARY
CAS
1072833-77-2
Created by admin on Mon Oct 21 20:56:39 UTC 2019 , Edited by admin on Mon Oct 21 20:56:39 UTC 2019
PRIMARY
RXCUI
1723735
Created by admin on Mon Oct 21 20:56:39 UTC 2019 , Edited by admin on Mon Oct 21 20:56:39 UTC 2019
PRIMARY RxNorm
NCI_THESAURUS
C97940
Created by admin on Mon Oct 21 20:56:39 UTC 2019 , Edited by admin on Mon Oct 21 20:56:39 UTC 2019
PRIMARY
LactMed
1072833-77-2
Created by admin on Mon Oct 21 20:56:39 UTC 2019 , Edited by admin on Mon Oct 21 20:56:39 UTC 2019
PRIMARY
DRUG BANK
DB09570
Created by admin on Mon Oct 21 20:56:39 UTC 2019 , Edited by admin on Mon Oct 21 20:56:39 UTC 2019
PRIMARY
EVMPD
SUB121332
Created by admin on Mon Oct 21 20:56:39 UTC 2019 , Edited by admin on Mon Oct 21 20:56:39 UTC 2019
PRIMARY
WIKIPEDIA
Ixazomib
Created by admin on Mon Oct 21 20:56:39 UTC 2019 , Edited by admin on Mon Oct 21 20:56:39 UTC 2019
PRIMARY
INN
9411
Created by admin on Mon Oct 21 20:56:39 UTC 2019 , Edited by admin on Mon Oct 21 20:56:39 UTC 2019
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
CYP 1A2 CONTRIBUTES FOR 26% OF IXAZOMIB METABOLISM
METABOLIC ENZYME -> SUBSTRATE
At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (< 1%).
EXCRETED UNCHANGED
62% of the 4.1 MG dose recovered in the urine (3.3% as unchanged drug)
AMOUNT EXCRETED
URINE
METABOLIC ENZYME -> SUBSTRATE
At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (< 1%).
METABOLIC ENZYME -> SUBSTRATE
At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (< 1%).
METABOLIC ENZYME -> SUBSTRATE
At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (< 1%).
METABOLIC ENZYME -> SUBSTRATE
CYP 3A CONTRIBUTES FOR 42% OF IXAZOMIB METABOLISM
MAJOR
METABOLIC ENZYME -> SUBSTRATE
CYP 2B6 CONTRIBUTES FOR 16% OF IXAZOMIB METABOLISM
BINDER->LIGAND
BINDING
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Volume of Distribution PHARMACOKINETIC
Tmax PHARMACOKINETIC ORAL ADMINISTRATION

Biological Half-life PHARMACOKINETIC