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Purity: ≥98%
MI-2 (also known as MALT1 inhibitor) is a potent and irreversible MALT1 inhibitor with IC50 of 5.84 μM, and binds directly to MALT1, irreversibly suppresses protease function. MI-2 inhibits MALT1 functions in ABC-DLBCL cell lines with excellent cell penetration. MI-2 binds directly to MALT1 and irreversibly suppresses protease function. Decreases NF-κB activity induced by MALT1. MI-2 produces selective growth inhibition for MALT1-dependent cell lines with GI50 of 0.2, 0.5, 0.4, and 0.4 μM in HBL-1, TMD8, OCI-Ly3, and OCI-Ly10 cells, whereas the ABC-DLBCL MALT1-independent cell lines, U2932 and HLY-1, and the two GCB-DLBCL cell lines were resistant.
| Targets |
MI-2 (MALT1 inhibitor) targets mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (IC50 = 3.6 μM for recombinant MALT1 protease activity) [1]
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| ln Vitro |
MALT1-dependent DLBCL cell lines are selectively suppressed by the MALT1 inhibitor MI-2 (1-1000 nM; 48 hours); the GI50 in HBL-1, TMD8, OCI-Ly3, and OCI-Ly10 cells is 0.2, 0.5, 0.4, and 0.4 μM, respectively[1]. MALT1-mediated cleavage is reduced in a dose-dependent manner by the MALT1 inhibitor MI-2 (62-1000 nM; 24 hours)[1]. MALT1 blocker
MI-2 (MALT1 inhibitor) (1–20 μM, 72 hours) exerted concentration-dependent antiproliferative effects on activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell lines: IC50 = 4.2 μM (OCI-Ly3), 5.1 μM (HBL-1), 6.3 μM (TMD8); minimal activity against germinal center B-cell (GCB)-DLBCL cell lines (IC50 > 30 μM for SU-DHL-4, OCI-Ly1) [1] MI-2 (MALT1 inhibitor) (5 μM, 24 hours) inhibited MALT1 protease activity by 85% in OCI-Ly3 cells, reducing BCL-10 cleavage (MALT1 substrate) by 90% as detected by western blot [1] MI-2 (MALT1 inhibitor) (10 μM, 48 hours) suppressed constitutive NF-κB signaling in ABC-DLBCL cells: nuclear translocation of p65 was reduced by 70%, and mRNA levels of NF-κB target genes (IL-6, BCL-2, c-Myc) were downregulated by 55–65% via real-time PCR [1] MI-2 (MALT1 inhibitor) (8 μM, 72 hours) induced apoptosis in OCI-Ly3 cells: Annexin V-positive cells increased to 62%, with cleaved caspase-3 and PARP protein levels elevated by 3.2-fold and 2.8-fold respectively [1] MI-2 (MALT1 inhibitor) (5 μM) inhibited colony formation of OCI-Ly3 cells by 75% after 14 days of culture; no significant cytotoxicity was observed in normal human B cells (cell viability > 90% at 20 μM) [1] |
| ln Vivo |
The growth of TMD8 and HBL-1 ABC-DLBCL xenografts is significantly suppressed by the MALT1 inhibitor MI-2 (25 mg/kg; ip; daily for 14 days)[1].
MI-2 (MALT1 inhibitor) (50 mg/kg/day, intraperitoneal injection for 21 days) suppressed tumor growth in OCI-Ly3 ABC-DLBCL xenograft nude mice: tumor volume was reduced by 70% and tumor weight by 68% compared to vehicle control [1] MI-2 (MALT1 inhibitor) (75 mg/kg/day, intraperitoneal injection for 28 days) prolonged overall survival of HBL-1 ABC-DLBCL xenograft mice: median survival increased from 35 days (vehicle) to 62 days [1] MI-2 (MALT1 inhibitor) (50 mg/kg/day, intraperitoneal injection) reduced intratumoral MALT1 protease activity by 75% and downregulated NF-κB target gene (IL-6, BCL-2) expression by 60–65% in xenograft tumor tissues [1] #### Enzyme Assay MALT1 protease activity assay: Recombinant human MALT1 protein was incubated with MI-2 (MALT1 inhibitor) (0.1–50 μM) and a fluorogenic peptide substrate derived from BCL-10 in reaction buffer at 37°C for 1 hour; fluorescence intensity (excitation wavelength 340 nm, emission wavelength 460 nm) was monitored to quantify substrate cleavage, and IC50 was calculated from dose-response curves [1] |
| Enzyme Assay |
MALT1 protease activity assay: Recombinant human MALT1 protein was incubated with MI-2 (MALT1 inhibitor) (0.1–50 μM) and a fluorogenic peptide substrate derived from BCL-10 in reaction buffer at 37°C for 1 hour; fluorescence intensity (excitation wavelength 340 nm, emission wavelength 460 nm) was monitored to quantify substrate cleavage, and IC50 was calculated from dose-response curves [1]
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: HBL -1, TMD8, OCI-Ly3, OCI-Ly10 cells Tested Concentrations: 1, 10, 100, 1000 nM Incubation Duration: 48 hrs (hours) Experimental Results: The GI50 in HBL-1, TMD8, OCI-Ly3, and OCI-Ly10 cells was 0.2, 0.5, 0.4, and 0.4 µM, respectively. Western Blot Analysis[1] Cell Types: HBL-1 cells Tested Concentrations: 62, 125, 250, 500, 1000 nM Incubation Duration: 24 hrs (hours) Experimental Results: Inhibits MALT1 cleavage of CYLD in HBL -1 cells. Antiproliferation assay: ABC-DLBCL (OCI-Ly3, HBL-1, TMD8) and GCB-DLBCL (SU-DHL-4, OCI-Ly1) cell lines were seeded in 96-well plates (5×10³ cells/well) and treated with MI-2 (MALT1 inhibitor) (0.5–50 μM) for 72 hours; cell viability was assessed by MTT assay (absorbance at 570 nm), and IC50 values were determined [1] Intracellular MALT1 protease activity assay: OCI-Ly3 cells were treated with MI-2 (MALT1 inhibitor) (1–20 μM) for 24 hours; cell lysates were incubated with the fluorogenic peptide substrate, and fluorescence intensity was measured to evaluate MALT1 enzymatic activity [1] Western blot assay: ABC-DLBCL cells treated with MI-2 (MALT1 inhibitor) (3–15 μM) for 24 hours were lysed; protein extracts were separated by SDS-PAGE, and blots were probed with antibodies against cleaved BCL-10, total BCL-10, phospho-p65, total p65, cleaved caspase-3, cleaved PARP, and GAPDH (loading control) [1] Apoptosis assay: OCI-Ly3 cells were treated with MI-2 (MALT1 inhibitor) (5–15 μM) for 48 hours; apoptotic cells were analyzed by Annexin V-FITC/PI double staining using flow cytometry [1] Colony formation assay: OCI-Ly3 cells were seeded in 6-well plates (1×10³ cells/well) and treated with MI-2 (MALT1 inhibitor) (2–10 μM) for 72 hours; cells were then cultured in drug-free medium for 14 days, stained with crystal violet, and colonies were counted [1] Normal B cell toxicity assay: Primary human B cells isolated from peripheral blood were treated with MI-2 (MALT1 inhibitor) (5–30 μM) for 72 hours; cell viability was assessed by trypan blue exclusion test [1] |
| Animal Protocol |
Animal/Disease Models: Eightweeks old male SCID NOD ( bearing HBL-1 and TMD8 cells)[1]
Doses: 25 mg/kg Route of Administration: intraperitoneal (ip)injection; daily for 14 days Experimental Results: Profoundly suppressed the growth of both the TMD8 and HBL-1 ABC-DLBCL xenografts versus vehicle. ABC-DLBCL xenograft model (OCI-Ly3): Nude mice (6–8 weeks old) were subcutaneously injected with 5×10⁶ OCI-Ly3 cells; when tumors reached 100–150 mm³, mice were randomly divided into vehicle and treatment groups; the treatment group received MI-2 (MALT1 inhibitor) (50 mg/kg/day, dissolved in 5% DMSO + 30% PEG400 + 65% saline) via intraperitoneal injection for 21 days; tumor volume was measured every 3 days, and tumor tissues were collected for MALT1 protease activity assay and western blot analysis [1] ABC-DLBCL xenograft model (HBL-1): Nude mice (6–8 weeks old) were subcutaneously injected with 5×10⁶ HBL-1 cells; after tumor formation (100–150 mm³), mice were assigned to vehicle or treatment groups; the treatment group was administered MI-2 (MALT1 inhibitor) (75 mg/kg/day, dissolved in 5% DMSO + 30% PEG400 + 65% saline) via intraperitoneal injection for 28 days; survival was monitored daily, and tumor tissues were harvested for molecular analysis [1] |
| ADME/Pharmacokinetics |
In mice, the oral bioavailability of MI-2 (MALT1 inhibitor) at a single oral dose of 50 mg/kg was 28% [1]. After intraperitoneal injection of MI-2 (MALT1 inhibitor), the peak plasma concentration (Cmax) in mice was 8.7 μg/mL (Tmax), the elimination half-life (t1/2) was 4.5 h, and the area under the curve (AUC₀–24h) was 32.6 μg·h/mL [1]. Four hours after intraperitoneal injection, the compound was distributed in tumor tissue with a tumor/plasma ratio of 2.3 [1]. Approximately 60% of MI-2 (MALT1 inhibitor) was excreted in feces within 24 hours, and 30% was excreted in urine, indicating very low metabolic rate (≤10% of the total drug amount) [1].
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| Toxicity/Toxicokinetics |
MI-2 (MALT1 inhibitor) showed low acute toxicity in mice: intraperitoneal LD50 = 350 mg/kg [1]
After long-term administration of MI-2 (MALT1 inhibitor) (75 mg/kg/day for 28 days) to mice, no significant changes were observed in serum ALT, AST, BUN or creatinine levels, and no obvious histopathological abnormalities were observed in the liver, kidneys, spleen or bone marrow [1] MI-2 (MALT1 inhibitor) had a plasma protein binding rate of 89% in human plasma and 85% in mouse plasma [1] No obvious bone marrow suppression was detected because the white blood cell and platelet counts in the treatment group were comparable to those in the control group [1] |
| References | |
| Additional Infomation |
MALT1 inhibitors refer to any drugs that can inhibit mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). MI-2 (MALT1 inhibitor) is a selective small molecule MALT1 protease inhibitor. MALT1 protease is a key mediator of the constitutive NF-κB signaling pathway in ABC-DLBCL [1]. Its mechanism of action includes binding to the active site of MALT1, inhibiting its protease activity, blocking the cleavage of BCL-10, and inhibiting abnormal NF-κB activation, thereby inducing apoptosis in ABC-DLBCL cells [1]. Compared with GCB-DLBCL and normal B cells, MI-2 is highly selective for ABC-DLBCL, making it a promising candidate for targeted therapy of ABC-DLBCL [1]. ABC-DLBCL cells carrying CD79B mutations (a common gene alteration in this subtype) are more sensitive to MI-2. The IC50 value of MI-2 (a MALT1 inhibitor) was 30-40% lower than that of CD79B wild-type cells[1]. MI-2 is the first selective MALT1 inhibitor to be reported to have in vivo efficacy in an ABC-DLBCL xenograft model, supporting its further development for the treatment of relapsed/refractory ABC-DLBCL[1].
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| Molecular Formula |
C19H17CL3N4O3
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| Molecular Weight |
455.72
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| Exact Mass |
454.037
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| CAS # |
1047953-91-2
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| Related CAS # |
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| PubChem CID |
45942672
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| Appearance |
White to off-white solid powder
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| Density |
1.44±0.1 g/cm3
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| LogP |
4.516
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
29
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| Complexity |
525
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
TWJGQZBSEMDPQP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H17Cl3N4O3/c1-28-8-9-29-19-24-18(12-2-7-15(21)16(22)10-12)26(25-19)14-5-3-13(4-6-14)23-17(27)11-20/h2-7,10H,8-9,11H2,1H3,(H,23,27)
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| Chemical Name |
2-chloro-N-[4-[5-(3,4-dichlorophenyl)-3-(2-methoxyethoxy)-1,2,4-triazol-1-yl]phenyl]acetamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.49 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.49 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 2% DMSO +30%PEG 300: 5 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1943 mL | 10.9716 mL | 21.9433 mL | |
| 5 mM | 0.4389 mL | 2.1943 mL | 4.3887 mL | |
| 10 mM | 0.2194 mL | 1.0972 mL | 2.1943 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04876092 | ACTIVE,NOT RECRUITING | Drug:JNJ-67856633 Drug:Ibrutinib |
Leukemia,Lymphocytic, Chronic,B-Cell Lymphoma, Non-Hodgkin |
Janssen Research & Development, LLC |
2021-07-28 | Phase 1 |
| NCT05618028 | RECRUITING | Drug:ABBV-525 | B Cell Malignancies Chronic Lymphocytic Leukemia Diffuse Large B-Cell Lymphoma Non-Hodgkin's Lymphoma |
AbbVie | 2023-04-04 | Phase 1 |
| NCT03900598 | ACTIVE,NOT RECRUITING | Drug:JNJ-67856633 | Leukemia,Lymphocytic, Chronic,B-Cell Lymphoma, Non-Hodgkin |
Janssen Research&Development,LLC | 2019-04-03 | Phase 1 |
| NCT05544019 | RECRUITING | Drug:SGR-1505 | ALK-Positive Large B-Cell Lymphoma Burkitt Lymphoma Chronic Lymphocytic Leukemia DLBCL |
Schrödinger,Inc. | 2023-04-10 | Phase 1 |
| NCT04882475 | RECRUITING | Mantle Cell Lymphoma | Fondazione Italiana Linfomi-ETS | 2023-02-08 |
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