HH2853
HH2853 is an orally active EZH1/EZH2 inhibitor, with an IC50 of 9.26 nM for EZH1 and IC50 values ranging from 2.21 to 3.75 nM for both wild-type and mutant EZH2. HH2853 simultaneously inhibits the methyltransferase activities of EZH1 and EZH2, blocks the compensatory pathway that arises following EZH2 inhibition, and reduces H3K27me3 levels. HH2853 upregulates the expression of c-Myc and TfR-1 to induce intracellular iron accumulation, and stabilizes GPX4 via HSPA5 to suppress ferroptosis. HH2853 combined with Erastin (HY-15763) synergistically inhibits EZH2 wild-type DLBCL cell proliferation. HH2853 alone shows weak activity against EZH2 wild-type DLBCL and is well tolerated. HH2853 is applicable for research related to diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, epithelioid sarcoma, and follicular lymphoma.
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研究用途以外に使用した場合、当社は一切の責任を負いかねます。
- CAS 番号: 2202678-04-2
- 分子式: C31H36F3N7O3
- 分子量:611.66
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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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Help & FAQs
Histone Methyltransferase アイソフォーム固有の製品をすべて表示
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生物活性
製品説明
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EZH1 9.26 nM (IC50) |
EZH2 Y641F mutant type 2.21 nM (IC50) |
EZH2 Y641N 2.65 nM (IC50) |
EZH2 Y641C 2.62 nM (IC50) |
EZH2 A677G 3.75 nM (IC50) |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
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| U2932 | IC50 |
>10 μM
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Antiproliferative activity against human EZH2 wild-type DLBCL U-2932 cells assessed as reduction in cell viability incubated for 6 days by CCK-8 assay.
Antiproliferative activity against human EZH2 wild-type DLBCL U-2932 cells assessed as reduction in cell viability incubated for 6 days by CCK-8 assay.
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37225847 |
体外実験
HH2853 (6 days) inhibits the proliferation of EZH2G12C-mutant DLBCL cells, with an IC50 value at the low nM level; however, it exhibits weak activity against EZH2 wild-type DLBCL cells (such as U-2932 and WILL-2), with an IC50 value >10 μM[1].
HH2853 (0.2-1 μM; 3-6 days) induces distinct molecular changes in both EZH2 inhibitor-insensitive (U-2932, WILL-2) and -sensitive (KARPAS-422, Pfeiffer) DLBCL cells: it upregulates H3K27ac, c-Myc, TfR-1, labile iron, GPX4, and HSPA5 in insensitive cells, while downregulating these markers in sensitive cells (with the exception of H3K27me3, which is reduced in all cell lines)[1].
HH2853 (0.25-4 μM; 4-6 days) acts synergistically with ferroptosis inducers (RSL3 (HY-100218A); ML162 (HY-100002)) to trigger ferroptosis and reduce cell viability in U-2932, WILL-2, and OCI-LY10 diffuse large B-cell lymphoma (DLBCL) cells that are insensitive to EZH2 inhibitors; in contrast, GPX4 knockout restores the sensitivity of U-2932 cells to HH2853[1].
HH2853 (4 h) potently inhibits the catalytic activity of wild-type EZH2, EZH2G12C, and EZH1 in a cell-free HTRF assay, with IC50 values ranging from 2.21 nM to 9.26 nM[1].
HH2853 (compound 199) inhibits the methyltransferase activity of the EZH2 Y641F mutant, with an IC50 ≤ 100 nM[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:EZH2i-resistant DLBCL cells (U-2932, WILL-2)
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Concentration:1 μM
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Incubation Time:3 days
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Result:Detected GPX4, DHODH, and FSP1 protein levels; HH2853 upregulated GPX4 protein levels.
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Cell Line:EZH2i-resistant DLBCL cells (U-2932, WILL-2)
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Concentration:1 μM
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Incubation Time:3 days
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Result:Measured GPX4 mRNA levels; HH2853 did not affect GPX4 mRNA levels.
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Cell Line:EZH2i-resistant U-2932 cells
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Concentration:1 μM
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Incubation Time:3 days
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Result:Measured HSPA5 mRNA levels; HH2853 upregulated HSPA5 mRNA levels.
体内実験
HH2853 (100 mg/kg; oral administration; once daily; for 14-15 consecutive days) fails to inhibit the growth of U-2932 diffuse large B-cell lymphoma (DLBCL) xenografts, but increases iron levels in tumor tissues[1].
HH2853 (100 mg/kg; p.o.; once daily; for 14 consecutive days) exhibits weak single-agent activity against WILL-2 DLBCL xenografts, but when combined with 10 mg/kg Erastin (HY-15763), it synergistically inhibits tumor growth and reverses HH2853-induced GPX4 upregulation and iron accumulation[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:SCID mice[1]
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Dosage:5 mg/kg; 10 mg/kg; 20 mg/kg
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Administration:p.o.; daily; 21 days
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Result:Reduced relative tumor volume (RTV) compared to vehicle control at 5 mg/kg.
Further reduced RTV at 10 mg/kg.
Resulted in the greatest reduction in RTV at 20 mg/kg, with stronger tumor growth inhibition than 50 mg/kg EPZ-6438.
Exhibited no body weight loss across all doses.
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Animal Model:SCID mice[1]
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Dosage:100 mg/kg
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Administration:p.o.; daily;14 or 15 days
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Result:Did not inhibit U-2932 xenograft growth.
Increased tumor tissue iron content compared to vehicle control.
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Animal Model:SCID mice[1]
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Dosage:100 mg/kg (monotherapy); 100 mg/kg + 10 mg/kg Erastin (combination)
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Administration:p.o.; daily; 14 days (monotherapy); p.o.; daily (HH2853) + i.p.; daily (erastin) (combination)
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Result:Reduced WILL-2 xenograft growth with an inhibitory rate of 22.85% as monotherapy.
Increased tumor tissue levels of TfR-1, GPX4, HSPA5, and H3K27ac as monotherapy.
Decreased tumor tissue H3K27me3 levels as monotherapy.
Elevated tumor tissue iron content as monotherapy.
Reduced tumor growth with an inhibitory rate of 53.85% (greater than either monotherapy) in combination with erastin.
Reversed HH2853-induced GPX4 upregulation in tumor tissues in combination with erastin.
Reduced tumor tissue iron content compared to HH2853 monotherapy in combination with erastin.
化学情報
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CAS 番号 2202678-04-2
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分子量 611.66
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分子式 C31H36F3N7O3
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SMILES
O=C(C1=CC2=C(C3=NN=C(C)C=C3)C=CN2C(C(C)N4CCN(CC(F)(F)F)CC4)=C1C)NCC5=C(OC)C=C(C)NC5=O
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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)
HH2853 関連分類
HY-187629 関連分類
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