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Cat. No.: HY-187629

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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.

For research use only. We do not sell to patients.

CAS No.: 2202678-04-2
Formula: C₃₁H₃₆F₃N₇O₃
Molecular Weight:611.66

Storage:

Please store the product under the recommended conditions in the Certificate of Analysis.

HH2853 Chemical Structure

CAS No.: 2202678-04-2

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Use of MCE Products

Strong Fluorescence Signal / Multi-Disciplinary Applications / High Fluorescence Specificity

Biological Activity
- Description
- IC₅₀ & Target
- Cellular Effect
- In Vitro
- In Vivo
Chemical Information
Purity & Documentation
References
Calculators
Help & FAQs
Classifications
Bioz

Biological Activity

Description

IC₅₀ & Target

^[1]^[2]

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)

All Histone Methyltransferase Isoforms :

Cellular Effect

Cell Line	Type	Value	Description	References
U2932	IC50	>10 μM	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.	37225847

In Vitro

Anti-cancerOxidative StressFerroptosisOthers

Anti-cancer

HH2853 (6 days) inhibits the proliferation of EZH2^G12C-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].

Anti-cancer

Oxidative Stress

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].

Anti-cancer

Ferroptosis

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].

Others

HH2853 (4 h) potently inhibits the catalytic activity of wild-type EZH2, EZH2^G12C, 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.

Western Blot Analysis^[1]

Cell Line:

EZH2i-resistant DLBCL cells (U-2932, WILL-2)
Concentration:

1 μM
Incubation Time:

3 days
Result:

Detected GPX4, DHODH, and FSP1 protein levels; HH2853 upregulated GPX4 protein levels.

RT-PCR^[1]

Cell Line:

EZH2i-resistant DLBCL cells (U-2932, WILL-2)
Concentration:

1 μM
Incubation Time:

3 days
Result:

Measured GPX4 mRNA levels; HH2853 did not affect GPX4 mRNA levels.

RT-PCR^[1]

Cell Line:

EZH2i-resistant U-2932 cells
Concentration:

1 μM
Incubation Time:

3 days
Result:

Measured HSPA5 mRNA levels; HH2853 upregulated HSPA5 mRNA levels.

In Vivo

Anti-cancerFerroptosis

Anti-cancer

HH2853 (5-20 mg/kg; p.o.; once daily; for 21 consecutive days) potently and dose-dependently inhibits the growth of Pfeiffer diffuse large B-cell lymphoma (DLBCL) xenografts^[1].
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].

Anti-cancer

Ferroptosis

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.

Animal Model:

SCID mice^[1]
Dosage:

5 mg/kg; 10 mg/kg; 20 mg/kg
Administration:

p.o.; daily; 21 days
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.

Animal Model:

SCID mice^[1]
Dosage:

100 mg/kg
Administration:

p.o.; daily;14 or 15 days
Result:

Did not inhibit U-2932 xenograft growth.
Increased tumor tissue iron content compared to vehicle control.

Animal Model:

SCID mice^[1]
Dosage:

100 mg/kg (monotherapy); 100 mg/kg + 10 mg/kg Erastin (combination)
Administration:

p.o.; daily; 14 days (monotherapy); p.o.; daily (HH2853) + i.p.; daily (erastin) (combination)
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.

Related Protocols :

Chemical Information

CAS No. 2202678-04-2
Molecular Weight 611.66
Formula C₃₁H₃₆F₃N₇O₃
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
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

Purity & Documentation

Handling Instructions (2659 KB)

References

[1]. Yu L, et al. Dysregulation of iron homeostasis by TfR-1 renders EZH2 wild type diffuse large B-cell lymphoma resistance to EZH2 inhibition. Acta pharmacologica Sinica. 2023 Oct;44(10):2113-2124.

[2]. Chen X, et al. Pyrido five-element aromatic ring compound, preparation method therefor and use thereof: U.S. Patent 10,968,215[P]. 2021-4-6.

Calculators

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Help & FAQs

How should lyophilized recombinant proteins be reconstituted and stored?

1. Before opening the cap, centrifuge the vial at 13000 rpm for 20-30 seconds. This step will ensure that any lyophilized powder that may have adhered to the cap or walls is collected at the bottom of the vial, minimizing the risk of product loss.

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100 mg

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Biological Activity
- Description
- IC₅₀ & Target
- In Vitro
- In Vivo
Chemical Information
Purity & Documentation
References

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HH2853

All Histone Methyltransferase Isoforms