MS2133
MS2133 is a VHL-recruiting DOT1L PROTAC degrader. MS2133 possesses antiproliferative activity with a human DOT1L IC50 of 4.6 nM, forms a ternary complex with DOT1L and VHL E3 ligase to drive DOT1L ubiquitination and subsequent proteasomal degradation without affecting DOT1L mRNA transcription, inhibits the proliferation of mixed lineage leukemia-rearranged leukemia cells and downregulates H3K79Me2, restrains proliferation of both tumor and normal cells but lacks cytotoxicity against normal cells, and can be used for the research of mixed lineage leukemia-rearranged leukemia.
(Pink: DOT1L ligand (HY-173423); Blue: VHL ligand (HY-47070); Black: linker).
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- Formule: C58H66ClF3N14O11S2
- Masse moléculaire:1291.81
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
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Activité biologique
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DOT1L 4.6 nM (IC50) |
DOT1L 25 nM (DC50) |
DOT1L 56 nM (DC50) |
MS2133 (compound 13) (0.3-3 μM; 24 h) potently reduces DOT1L protein levels in THP-1 MLL-r leukemia cells, achieving 70% degradation at 0.3 μM and 77% degradation at 3 μM after 24 h treatment[1].
MS2133 (0.5 nM-3.3 μM; 24 h) induces potent concentration-dependent DOT1L degradation in THP-1 cells (DC50 = 56 nM, Dmax = 69%) after 24 h treatment[1].
MS2133 (0.2 nM-3.0 μM; 24 h) induces potent concentration-dependent DOT1L degradation in MV4-11 cells (DC50 = 25 nM, Dmax = 93%) after 24 h treatment[1].
MS2133 (3 μM; 1-48 h) induces time-dependent DOT1L degradation in THP-1 (maximal at 24 h) and MV4-11 (near-complete at 48 h) MLL-r leukemia cells, with downstream H3K79Me2 reduction delayed relative to DOT1L degradation in both cell lines[1].
MS2133 (3 μM; 4-8 h) -induced DOT1L degradation in THP-1 MLL-r leukemia cells occurs via the ubiquitin-proteasome system, as pre-treatment with proteasome inhibitor or NEDD8-activating enzyme inhibitor blocks degradation[1].
MS2133 (3 μM; 24 h) -induced DOT1L degradation in THP-1 MLL-r leukemia cells is VHL-dependent, as co-treatment with a competing VHL ligand blocks degradation[1].
MS2133 (3 μM; 24 h) does not affect DOT1L mRNA expression in MV4-11 and MOLM-13 MLL-r leukemia cells after 24 h treatment at 3 μM[1].
MS2133 (0.3-3 μM; 24 h) -induced DOT1L degradation in THP-1 MLL-r leukemia cells requires DOT1L binding[1].
MS2133 (0.004-3.3 μM) potently inhibits DOT1L methyltransferase activity, achieving >95% inhibition at 4.6 nM[1].
MS2133 (10 μM) is highly selective for DOT1L, showing no significant inhibition of 12 other tested DNA and protein methyltransferases at 10 μM[1].
DOT1L degrader (0.3-3 µM; 24 h) induces dose-dependent degradation of DOT1L protein in MOLM-13 cells after 24-hour treatment at 0.3 µM and 3 µM[1].
MS2133 (3 µM; 24 h) at 3 µM for 24 hours does not significantly alter DOT1L mRNA levels in MOLM-13 cells[1].
DOT1L degrader (0.3-3 µM; 24 h) induces dose-dependent degradation of DOT1L and reduction of H3K79Me2 in MCF10A cells[1].
MS2133 (0.23-30.0 µM; 7 days) exhibits minimal antiproliferative activity in MCF10A cells[1].
DOT1L degrader MS2133 (0.3-3 µM; 24 h) induces dose-dependent degradation of DOT1L (without altering H3K79Me2 levels) in PNT2 cells[1].
MS2133 (0.12-30.0 µM; 7 days) exhibits minimal antiproliferative activity in PNT2 cells[1].
MS2133 (30 nM-15 μM; 7 days) potently inhibits growth of DOT1L-dependent MV4-11 (GI50 = 212 nM) and MOLM-13 MLL-r leukemia cells after 7 days of treatment, while showing no toxicity to THP-1 cells or normal MCF10A and PNT2 cells[1].
MS2133 (0.06-15.0 µM; 7 days) exhibits dose-dependent antiproliferative activity in MOLM-13 cells[1].
MS2133 (0.01-30.0 µM; 7 days) exhibits dose-dependent antiproliferative activity in THP-1 cells over a 7-day treatment period at concentrations ranging from 0.01 µM to 30.0 µM[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:THP-1 mixed lineage leukemia-rearranged (MLL-r) leukemia cells
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Concentration:0.3 μM, 3 μM
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Incubation Time:24 h
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Result:Reduced DOT1L protein levels by 70% at 0.3 μM relative to DMSO control.
Reduced DOT1L protein levels by 77% at 3 μM relative to DMSO control.
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Cell Line:THP-1 and MV4-11 MLL-r leukemia cells
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Concentration:3.3 μM down to ~0.5 nM (3-fold serial dilutions, THP-1); 3 μM down to ~0.2 nM (3-fold serial dilutions, MV4-11)
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Incubation Time:24 h
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Result:Induced DOT1L degradation in THP-1 cells with a DC50 of 56 nM and a Dmaxof 69%.
Induced DOT1L degradation in MV4-11 cells with a DC50 of 25 nM and a Dmax of 93%.
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Cell Line:THP-1 and MV4-11 MLL-r leukemia cells
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Concentration:3 μM
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Incubation Time:1-24 h (THP-1); 1-48 h (MV4-11)
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Result:Substantially reduced DOT1L protein levels in THP-1 cells by 1 h, with maximum degradation at 24 h.
Significantly reduced H3K79Me2 levels in THP-1 cells only after 24 h.
Induced pronounced DOT1L degradation in MV4-11 cells starting at 2 h, with near-complete degradation at 48 h.
Reduced H3K79Me2 levels in MV4-11 cells starting at 2 h, with a substantial reduction at 48 h.
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Cell Line:THP-1 MLL-r leukemia cells
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Concentration:3 μM
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Incubation Time:1 h (proteasome inhibitor pre-incubation); 4 h (MS2133 post proteasome inhibitor); 1 h (NEDD8-activating enzyme inhibitor pre-incubation); 8 h (MS2133 post NEDD8-activating enzyme inhibitor)
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Result:Rescued MS2133-mediated DOT1L degradation in THP-1 cells when pre-treated with proteasome inhibitor.
Rescued MS2133-mediated DOT1L degradation in THP-1 cells when pre-treated with NEDD8-activating enzyme inhibitor.
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Cell Line:THP-1 MLL-r leukemia cells
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Concentration:3 μM
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Incubation Time:24 h
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Result:Significantly rescued the reduction in DOT1L protein level induced by MS2133 when co-treated with VHL ligand.
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Cell Line:MV4-11 and MOLM-13 MLL-r leukemia cells
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Concentration:3 μM
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Incubation Time:24 h
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Result:Did not significantly alter DOT1L mRNA levels in MV4-11 and MOLM-13 cells.
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Cell Line:THP-1 MLL-r leukemia cells
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Concentration:0.3 μM, 3 μM
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Incubation Time:24 h
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Result:Significantly reduced DOT1L protein levels.
Showed no effect on DOT1L protein levels when using modified negative control compound 17 with disrupted DOT1L binding.
Showed no induction of DOT1L degradation when using existing DOT1L inhibitors (compound 2 and EPZ-5676).
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Cell Line:MV4-11, MOLM-13, and THP-1 MLL-r leukemia cells; MCF10A and PNT2 normal cells
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Concentration:30 nM-15 μM (2-fold serial dilutions, MV4-11); serial dilutions (MOLM-13, THP-1, MCF10A, PNT2)
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Incubation Time:7 days
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Result:Significantly inhibited growth of MV4-11 cells with a GI50 of 212 nM.
Inhibited growth of MOLM-13 cells but was less potent than in MV4-11 cells.
Did not inhibit growth of THP-1 cells.
Showed no toxicity in MCF10A and PNT2 normal cells.
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Cell Line:MOLM-13
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Concentration:0.3 µM, 3 µM
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Incubation Time:24 h
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Result:Reduced DOT1L protein levels in a dose-dependent manner relative to DMSO control.
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Cell Line:MOLM-13
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Concentration:3 µM
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Incubation Time:24 h
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Result:Showed no significant difference in DOT1L mRNA levels relative to DMSO control.
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Cell Line:MOLM-13
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Concentration:0.06 µM, 0.23 µM, 0.47 µM, 0.94 µM, 1.88 µM, 3.75 µM, 7.50 µM, 15.0 µM
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Incubation Time:7 days
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Result:Reduced normalized cell viability in a dose-dependent manner.
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Cell Line:THP-1
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Concentration:0.01 µM, 0.04 µM, 0.12 µM, 0.37 µM, 1.11 µM, 3.33 µM, 10.0 µM, 30.0 µM
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Incubation Time:7 days
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Result:Reduced normalized cell viability in a dose-dependent manner.
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Cell Line:MCF10A
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Concentration:0.3 µM, 3 µM
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Incubation Time:24 h
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Result:Reduced DOT1L and H3K79Me2 protein levels in a dose-dependent manner relative to DMSO control.
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Cell Line:MCF10A
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Concentration:0.23 µM, 0.47 µM, 0.94 µM, 1.88 µM, 3.75 µM, 7.50 µM, 15.0 µM, 30.0 µM
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Incubation Time:7 days
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Result:Caused minimal reduction in normalized cell viability across tested concentrations.
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Cell Line:PNT2
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Concentration:0.3 µM, 3 µM
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Incubation Time:24 h
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Result:Reduced DOT1L protein levels in a dose-dependent manner relative to DMSO control, with no change in H3K79Me2 levels.
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Cell Line:PNT2
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Concentration:0.12 µM, 0.23 µM, 0.47 µM, 0.94 µM, 1.88 µM, 3.75 µM, 7.50 µM, 15.0 µM, 30.0 µM
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Incubation Time:7 days
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Result:Caused minimal reduction in normalized cell viability across tested concentrations.
Chemical Information
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Masse moléculaire 1291.81
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Formule C58H66ClF3N14O11S2
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SMILES
O=C([C@H]1N(C([C@@H](NC(C2(F)CC2)=O)C(C)(C)C)=O)C[C@H](O)C1)N[C@H](C3=CC=C(C4=C(C)N=CS4)C=C3)CC(NCCCCCCNC(COC5=NC(N)=NC(NC6=CC(S(=O)(N)=O)=CC=C6N[C@H](C7=NC=CC=C7Cl)C8=C9OC(F)(F)OC9=CC=C8)=N5)=O)=O
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
MS2133 Related Classifications
HY-173422 Related Classifications
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