MS40
MS40 is a WDR5 PROTAC degrader with a DC50 of 42 nM in MV4;11 MLL-rearranged acute myeloid leukemia (AML) cells. MS40 induces WDR5 degradation dependent on WDR5, CRBN and the proteasome, dissociates the MLL/KMT2A complex from chromatin, reduces H3K4me2 levels, degrades IKZF1/IKZF3, the novel substrates of CRBN, inhibits the transcription of WDR5/MLL and IKZF target genes, and suppresses cancer cell growth. MS40 can be used in the research of MLL-rearranged acute myeloid leukemia, breast cancer, Burkholderia infection and cystic fibrosis-associated bacterial infections.
(Pink: WDR5 ligand (HY-141798); Blue: Cereblon ligand (HY-10984); Black: linker).
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- CAS 番号: 2407449-49-2
- 分子式: C52H61F3N10O7
- 分子量:995.10
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保管条件:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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生物活性
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化学情報
- 純度とドキュメンテーション
- 参考文献
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生物活性
製品説明
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WDR5 42 nM (DC50) |
体外実験
MS40 binds directly to purified WDR5 (KD = 125 nM) and CRBN-TBD (KD = 14.8 μM) and promotes formation of a cooperative WDR5:MS40:CRBN ternary complex (α = 1.96)[1].
MS40 (0.5 μM; 4 days) reduces global H3K4me2 levels and depletes MLL complex components (MLL, RBBP5, Menin) from chromatin in MV4;11 MLL-r AML cells[1].
MS40 (0-1.0 μM; 2-24 h) induces reversible, concentration- and time-dependent degradation of WDR5 (DC50 = 42 nM, D_max = 77%) and IKZF1/IKZF3 in MV4;11 MLL-r AML cells via a WDR5-, CRBN-, and proteasome-dependent mechanism[1].
MS40 (0.5-2.5 μM; 6 h) selectively downregulates WDR5, IKZF1, and LIMD1 proteins in MV4;11 MLL-r AML cells at the proteome-wide level[1].
MS40 (0.5 μM; 4 days) suppresses transcription of genes targeted by both WDR5:MLL complexes and IKZF factors at both nascent and steady-state levels in MV4;11 MLL-r AML cells[1].
MS40 (0-5.0 μM; 9 days) potently inhibits in vitro growth of MLL-r AML cell lines (GI50 = 180 nM to 540 nM) and WDR5-dependent breast cancer cell lines, but has no effect on non-MLL-r K562 leukemia cells[1].
MS40 (5 μM; 16-96 h) induces WDR5 degradation and suppresses in vitro growth of primary AML patient cells[1].
MS40 (18 h) potently inhibits growth of diverse Burkholderia strains, including Bcc isolates, B. mallei, and B. pseudomallei[2].
MS40 exhibits broad-spectrum bactericidal activity against common CF pathogens, with MIC values ranging from 0.25 to 32 µg/mL and corresponding MBC values mostly within 1- to 4-fold of the MIC[2].
MS40 (repeated for 24 days) does not select for multistep resistant mutants in Burkholderia cenocepacia K56-2 after 24 days of repeated subinhibitory exposure, maintaining a stable MIC of 4 µg/mL[2].
MS40 (4-16 µg/mL; up to 6 hours) is bactericidal against both replicating exponential phase and non-replicating stationary phase Burkholderia cenocepacia K56-2, with 4× MIC reducing stationary phase cell counts to near the limit of detection within 6 hours[2].
MS40 (8-16 µg/mL (persister kill); 20-40 µg/mL (persister formation); 3 hours (persister kill); 24 hours (persister formation)) kills Burkholderia cenocepacia K56-2 persister cells generated by ciprofloxacin and completely inhibits persister cell formation at 5× and 10× MIC after 24 hours[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:MV4;11 MLL-rearranged acute myeloid leukemia (MLL-r AML) cells
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Concentration:0-1.0 μM (18 h); 0.5 μM (2-24 h); 0.5 μM (6 h preceded by 2 h pre-treatment with 0-2.5 μM OICR-9429); 0.5 μM (6 h preceded by 2 h pre-treatment with 0.4 μM carfilzomib); 0.5-2.5 μM (6 h preceded by 2 h pre-treatment with 0.3 μM MLN4924); 0.5 μM (6 h preceded by 2 h pre-treatment with 0-5.0 μM pomalidomide); 0.5 μM (12 h followed by washout)
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Incubation Time:18 h; 2-24 h; 6 h (with 2 h pre-treatment); 12 h (followed by 0-48 h culture after washout)
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Result:Degraded WDR5 in a concentration-dependent manner, with a half-maximal degradation concentration (DC50) of 42 nM and a maximal degradation level (D_max) of 77% after 18 h treatment.
Induced time-dependent WDR5 degradation, with detectable effects as early as 2 h and sustained up to 24 h.
Had WDR5 degradation suppressed by pre-treatment with OICR-9429, carfilzomib, MLN4924, or pomalidomide.
Led to full recovery of WDR5 levels by 36 h after washout.
Degraded IKZF1 and IKZF3 (when expressed) in MV4;11 cells.
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Cell Line:Human leukemia cell lines (MV4;11, EOL1, RS4;11, K562), breast cancer cell lines (BT549, SUM149)
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Concentration:0-5.0 μM
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Incubation Time:9 days
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Result:Inhibited growth of MLL-r AML cell lines with GI50 values of 180 nM (MV4;11), 510 nM (EOL1), and 540 nM (RS4;11).
Exhibited no growth-inhibitory effect on K562 non-MLL-r leukemia cells (GI50 > 5000 nM).
Suppressed growth of BT549 and SUM149 breast cancer cells, which are WDR5-dependent but IKZF1-independent.
体内実験
MS40 (4-256 μg/mL; in liquid media; continuous exposure; 24 hours) shows low toxicity in healthy Caenorhabditis elegans, with a Survival100/MIC ratio of 4[2].
MS40 (1-10 mg/kg; i.p.; single injection) is well-tolerated in healthy Galleria mellonella larvae, with ≥80% survival across all tested doses up to 10 mg/kg over 72 hours[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:NSG-SGM3 mice (8-week-old; MLL-AF9 + AML patient-derived xenograft cells injected subcutaneously into flanks)[1]
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Dosage:100 mg/kg
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Administration:i.p.; once daily for 5 days per week
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Result:Significantly suppressed PDX tumor growth compared to vehicle.
Reduced WDR5 protein levels in tumor samples.
Suppressed expression of WDR5:MLL target genes including ribosome genes, BCL2, and RUNX3.
Caused no obvious body weight changes during treatment.
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Animal Model:DH26 (L4-stage, fed E. coli OP50)[2]
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Dosage:4 μg/mL, 8 μg/mL, 16 μg/mL, 32 μg/mL, 64 μg/mL, 128 μg/mL, 256 μg/mL
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Administration:in liquid media; continuous exposure; 24 hours
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Result:Achieved 100% survival at concentrations up to 16 μg/mL.
Decreased survival to 92.9% at 32 μg/mL, 94.7% at 64 μg/mL, 81.8% at 128 μg/mL, and 74.4% at 256 μg/mL.
Exhibited a Survival100/MIC ratio of 4.
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Animal Model:larvae (≈250 mg)[2]
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Dosage:1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg
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Administration:i.p.; single injection
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Result:Resulted in 100% survival at 24 hours, 96.7% at 48 hours, and 96.7% at 72 hours at 1 mg/kg.
Resulted in 90.0% survival at 24 hours, 80.0% at 48 hours, and 80.0% at 72 hours at 2 mg/kg.
Resulted in 96.7% survival at 24 hours, 93.3% at 48 hours, and 90.0% at 72 hours at 5 mg/kg.
Resulted in 90.0% survival at 24 hours, 83.3% at 48 hours, and 80.0% at 72 hours at 10 mg/kg.
化学情報
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CAS 番号 2407449-49-2
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分子量 995.10
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分子式 C52H61F3N10O7
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SMILES
O=C1C=C(C(F)(F)F)C(C(NC2=CC(C3=CC(CN4CCN(CC4)CCNC(CCCCCCCNC5=CC=CC(C(N6C7C(NC(CC7)=O)=O)=O)=C5C6=O)=O)=CC=C3)=CC=C2N8CCN(CC8)C)=O)=CN1
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輸送条件
Room temperature in continental US; may vary elsewhere.
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保管条件
Please store the product under the recommended conditions in the Certificate of Analysis.
純度とドキュメンテーション
参考文献
Calculators
濃度 (開始) × 体積 (開始) = 濃度 (終了) × 体積 (終了)
MS40 関連分類
HY-148829 関連分類
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