Home Ubiquitin E1 Activating inhibitor - NF-κB inhibitor - Apoptosis related activator TAK-243 (MLN7243) For research use only.

TAK-243 (MLN7243)

TAK-243 (MLN7243) is a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE) with an IC50 of 1 ± 0.2 nM in the UBCH10 E2 thioester assay. It has minimal inhibitory activity in a panel of kinase and receptor assays, as well as on human carbonic anhydrase type I and type II. TAK-243 (MLN7243) induces ER stress, abrogates NFκB pathway activation and promotes apoptosis.

TAK-243 (MLN7243) Chemical Structure

TAK-243 (MLN7243) Chemical Structure

CAS No. 1450833-55-2

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TAK-243 (MLN7243) Related Products

Signaling Pathway

E1 Activating Signaling Pathways

E1 Activating Signaling Pathway

Biological Activity

Description TAK-243 (MLN7243) is a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE) with an IC50 of 1 ± 0.2 nM in the UBCH10 E2 thioester assay. It has minimal inhibitory activity in a panel of kinase and receptor assays, as well as on human carbonic anhydrase type I and type II. TAK-243 (MLN7243) induces ER stress, abrogates NFκB pathway activation and promotes apoptosis.
Targets
NF-κB [2] UAE [1]
(Cell-free assay)
1 nM
In vitro
In vitro

TAK-243 treatment causes depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 has weaker inhibitory activity against other closely related E1 ubiquitin-like activating enzymes such as Fat10-activating enzyme (UBA6; 7 ± 3 nM), NEDD8-activating enzyme (NAE; 28 ± 11 nM), SUMO-activating enzyme (SAE; 850 ± 180 nM), ISG15-activating enzyme (UBA7; 5,300 ± 2,100 nM) and autophagy-activating enzyme (ATG7; >10,000 nM) than it does against UAE. TAK-243 inhibits UAE from transferring ubiquitin to an E2 enzyme. TAK-243 shows equally potent inhibition of the two E1 enzymes capable of activating ubiquitin (UBA6 and UAE), as indicated by comparable decreases in levels of charged USE1 and UBCH10. Downstream UAE pathway inhibition by TAK-243 is evident, as shown by a dose- and time-dependent loss of both polyubiquitin chains and mono-ubiquitylated histone H2B; however, TAK-243 treatment does not affect UAE (UBE1) protein levels. TAK-243 treatment also causes accumulation of short-lived proteins such as c-Jun, c-Myc, MCL1 and p53[1].
Cell Research Cell lines HCT-116 and WSU-DLCL2 cells
Concentrations 0.01, 0.10 or 1.00 μM
Incubation Time 1, 2, 4, 8, 16 and 24 h
Method

HCT-116 and WSU-DLCL2 cells are maintained in log-phase growth in McCoy's 5A modified or RPMI-1460 medium, respectively supplemented with 10% fetal bovine serum at 37℃ in a 5% CO2 incubator. Cells are grown in 6-well cell culture dishes and treated with DMSO (0.1%) or with 0.01, 0.10 or 1.00 μM TAK-243 for the times indicated. Whole-cell extracts are prepared using RIPA buffer.
Experimental Result Images Methods Biomarkers Images PMID
Western blot poly-ubiquitin / ubiquitin / cleaved PARP PERK / GRP78 / p-eIF2α / CHOP / p-IκBα / PARP c-Myc / Mcl-1 30617217
In Vivo
In vivo

TAK-243 treatment causes death of cancer cells and, in primary human xenograft studies. TAK-243 demonstrates broad antitumor activity in models of solid and hematological tumors[1].
Animal Research Animal Models SCID mice bearing WSU-DLCL2 NHL xenograft tumors
Dosages 12.5, 18.75 and 25 mg/kg
Administration IV
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT03816319 Not yet recruiting
Myelodysplastic Syndrome|Recurrent Acute Myeloid Leukemia|Refractory Acute Myeloid Leukemia|Refractory Chronic Myelomonocytic Leukemia|Refractory High Risk Myelodysplastic Syndrome
National Cancer Institute (NCI)
 August 30 2024 Phase 1
NCT02045095 Terminated
Advanced Malignant Solid Tumors
Millennium Pharmaceuticals Inc.|Takeda
 January 31 2014 Phase 1

Chemical Information & Solubility

Molecular Weight 519.52 Formula

C19H20F3N5O5S2
CAS No. 1450833-55-2 SDF --
Smiles N[S;v6](=O)(=O)OCC1CC(NC2=CC=NC3=CC(=N[N]23)C4=CC(=CC=C4)SC(F)(F)F)C(O)C1O
Storage (From the date of receipt) 3 years -20°C powder

In vitro
Batch:

DMSO : 100 mg/mL ( (192.48 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 25 mg/mL

Water : Insoluble


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