Referencia número: HY-168614

MGD-4

MGD-4 is an orally active cereblon-dependent molecular glue degrader with a phthalazinone scaffold. MGD-4 degrades the Ikaros family proteins IKZF1, IKZF2 and IKZF3 in a dose-dependent manner, with DC₅₀ values of 67.2 nM, 918.2 nM and 95.8 nM, respectively. MGD-4 exhibits weak degradation activity against CK1α. MGD-4 inhibits the viability of multiple myeloma (MM) and acute myeloid leukemia (AML) cells and induces cell apoptosis. MGD-4 is used for the research of multiple myeloma, acute myeloid leukemia, diffuse large B-cell lymphoma and related hematological malignancies .

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No. CAS: 2991817-99-1
Fòrmula: C₁₄H₁₆N₄O₃
Peso molecular:288.30

Almacenamiento:

4°C, protect from light

* In solvent : -80°C, 6 months; -20°C, 1 month (protect from light)

Data Sheet (297 KB)

MGD-4 Chemical Structure

No. CAS: 2991817-99-1

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Use of MCE Products

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

Actividad biológica
- Descripciòn
- IC₅₀ & Target
- Cellular Effect
- In Vitro
- Parmacokinetics
- In Vivo
Chemical Information
Pureza y Documentación
Referencias
Calculators
Help & FAQs
Classifications
Bioz

Actividad biológica

Descripciòn

IC₅₀ & Target

^[1]

IKZF1

67.2 nM (DC₅₀)

IZKF2

918.2 nM (DC₅₀)

IKZF3

95.8 nM (DC₅₀)

Ver todos los productos específicos de isoformas IKZF Family :

Cellular Effect

Cell Line	Type	Value	Description	References
RPMI-8226	IC50	1.15 μM	Antiproliferative activity against human RPMI-8226 multiple myeloma cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay. Antiproliferative activity against human RPMI-8226 multiple myeloma cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay.	39218923
NCI-H929	IC50	0.311 μM	Antiproliferative activity against human NCI-H929 multiple myeloma cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay. Antiproliferative activity against human NCI-H929 multiple myeloma cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay.	39218923
OPM-2	IC50	0.132 μM	Antiproliferative activity against human OPM-2 multiple myeloma cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay. Antiproliferative activity against human OPM-2 multiple myeloma cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay.	39218923
U-937	IC50	0.31 μM	Antiproliferative activity against human U937 acute myeloid leukemia cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay. Antiproliferative activity against human U937 acute myeloid leukemia cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay.	39218923
MOLM-13	IC50	0.402 μM	Antiproliferative activity against human MOLM-13 acute myeloid leukemia cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay. Antiproliferative activity against human MOLM-13 acute myeloid leukemia cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay.	39218923
MV4-11	IC50	0.183 μM	Antiproliferative activity against human MV-4-11 acute myeloid leukemia cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay. Antiproliferative activity against human MV-4-11 acute myeloid leukemia cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay.	39218923
KG-1	IC50	0.634 μM	Antiproliferative activity against human KG-1 acute myeloid leukemia cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay. Antiproliferative activity against human KG-1 acute myeloid leukemia cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay.	39218923
SKM-1	IC50	1.53 μM	Antiproliferative activity against human Skm-1 acute myeloid leukemia cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay. Antiproliferative activity against human Skm-1 acute myeloid leukemia cells assessed as reduction in cell viability incubated for 96 hrs by cell counting kit-8 (CCK-8) assay.	39218923

In Vitro

MGD-4 (96 h) inhibits the viability of MM and AML cells, with IC₅₀ values of 1.15, 0.311, 0.132, 0.31, 0.402, 0.183, 0.634, 1.53, and 1.36 μM in RPMI-8226, NCI-H929, OPM-2, U937, MOLM-13, MV-4-11, KG-1, Skm-1, and MUTZ-1 cells, respectively^[1].
MGD-4 (1 μM; 4 h) reduces IKZF1 protein levels in quantitative proteomic analysis of NCI-H929 cells^[1].
MGD-4 (10 nM-10 μM; 24 h) reduces the endogenous levels of IKZF1, IKZF2, and IKZF3 in NCI-H929 and MV-4-11 cells in a dose-dependent manner; MLN4924 (HY-70062) (1 μM; 1 h pre-incubation) blocks this degradation, supporting that this process depends on the activity of Cullin E3 ubiquitin ligase^[1].
MGD-4 (24 h) exhibits very weak degradation activity against HEK293T CK1α-HiBiT, with a DC₅₀ > 10 μM; treatment with 10 μM for 24 h also does not significantly reduce endogenous CK1α in NCI-H929 cells^[1].
MGD-4 (1, 10 μM; 3 days) induces Annexin V-positive apoptosis in wild-type NCI-H929 cells, while it does not induce significant apoptosis in CRBN^−/− NCI-H929 cells, indicating that the cellular effect of MGD-4 is CRBN-dependent^[1].
MGD-4 (1, 10 μM; 4 h) reduces the abundance of multiple proteins in global quantitative proteomics of NCI-H929 cells, including ZFP91, DTWD1, IKZF1, ZNFX1, ZMIZ2, MBD1, MBD3, and MNT^[1].
MGD-4 (0.1, 1 μM; 24 h) reduces the protein levels of ZFP91 and DTWD1 in NCI-H929 and MV-4-11 cells, while it does not induce the degradation of GSPT1^[1].
MGD-4 (0.1, 1 μM; 24 h) dose-dependently reduces the protein levels of ZNFX1, MBD1, MBD3, ZMIZ2, and MNT in NCI-H929 and MV-4-11 cells^[1].
MGD-4 (1 μM; 24 h) reduces ZMIZ2 mRNA levels in NCI-H929 cells, but does not decrease the mRNA levels of ZNFX1, MBD1, MBD3, and MNT, suggesting that the downregulation of the latter four proteins cannot be explained by the reduction of their corresponding mRNAs^[1].
MGD-4 (10 μM; 3 days) induces apoptosis in NCI-H929, MV-4-11 and WSU-DLCL-2 cells, with apoptosis rates of 52.1%, 41.0% and 16.5%, respectively^[1].
MGD-4 (24 h) degrades IKZF1, IKZF2, and IKZF3 in a dose-dependent manner in HEK293T cells stably expressing IKZF1-HiBiT, IKZF2-HiBiT, or IKZF3-HiBiT, with DC₅₀ values of 67.2 nM, 918.2 nM, and 95.8 nM, and D_max values of 84.9%, 64.6%, and 81.2%, respectively^[1].
MGD-4 (0.1, 1 μM; 0-24 h) induces time-dependent degradation of IKZF1, IKZF2 and IKZF3; after 4 h of incubation at 1 μM, IKZF1 is reduced by >70% and IKZF3 by >50%, while IKZF2 is reduced by >50% after 12 h of incubation^[1].
During the 500 ns molecular dynamics simulation of MGD-4, the distance between Tyr355 and His357 does not increase as observed for lenalidomide when forming a complex with CRBN, and CRBN Tyr355 does not undergo flipping. The IKZF1-MGD-4-CRBN docking model reveals that the glutarimide ring of MGD-4 is located on the surface of CRBN, while the phthalazinone ring faces the IKZF1 β-hairpin. The calculated ΔG of the CRBN complex recruited by MGD-4 is -87.76 kJ/mol^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Apoptosis Analysis^[1]

Cell Line:

NCI-H929, MV-4-11, WSU-DLCL-2
Concentration:

10 μM
Incubation Time:

3 days
Result:

Induced apoptosis in 52.1% of NCI-H929 cells.
Induced apoptosis in 41.0% of MV-4-11 cells.
Induced 16.5% apoptosis in WSU-DLCL-2 cells.

Western Blot Analysis^[1]

Cell Line:

NCI-H929, MV-4-11
Concentration:

10 nM, 100 nM, 1 μM, 10 μM
Incubation Time:

24 h (with optional 1 h MLN4924 pretreatment)
Result:

Exhibited higher endogenous degradation potency for IKZF1, IKZF2, and IKZF3 than immunomodulatory imide drug at micromolar concentrations in a Cullin-dependent manner.
Degradation of IKZF1, IKZF2, and IKZF3 was blocked by MLN4924 pretreatment.
Showed no efficacy in inducing endogenous CK1α degradation.

Western Blot Analysis^[1]

Cell Line:

NCI-H929
Concentration:

10 μM
Incubation Time:

24 h
Result:

Failed to markedly reduce endogenous CK1α protein.
Retained degradation activity toward Ikaros family proteins under the same experimental comparison.

Apoptosis Analysis^[1]

Cell Line:

NCI-H929 WT; NCI-H929 CRBN^−/−
Concentration:

1, 10 μM
Incubation Time:

3 days
Result:

Induced Annexin V-positive apoptosis in wild-type NCI-H929 cells.
Failed to induce appreciable apoptosis in CRBN^−/− NCI-H929 cells.
Demonstrated CRBN dependence of the cellular response.

RT-PCR^[1]

Cell Line:

NCI-H929
Concentration:

1 μM
Incubation Time:

24 h
Result:

Reduced ZMIZ2 mRNA expression.
Did not decrease ZNFX1 mRNA expression.
Did not decrease MBD1 mRNA expression.
Did not decrease MBD3 mRNA expression.
Did not decrease MNT mRNA expression.

Western Blot Analysis^[1]

Cell Line:

NCI-H929; MV-4-11
Concentration:

0.1, 1 μM
Incubation Time:

24 h
Result:

Dose-dependently reduced ZNFX1 protein.
Dose-dependently reduced MBD1 protein.
Dose-dependently reduced MBD3 protein.
Dose-dependently reduced ZMIZ2 protein.
Dose-dependently reduced MNT protein.

Parmacokinetics

Species	Dose	Route	T_1/2	C₀	AUC_0-t	AUC_0-inf	V_ss	CL	MRT_0-inf	C_max	T_max	F
Rat^[1]	1 mg/kg	i.v.	3.73 h	1583 ng/mL	814.1 μg·h/mL	826.9 μg·h/mL	1.73 L/kg	1.91 L/h/kg	0.90 h	/	/	/
Rat^[1]	3 mg/kg	p.o.	3.93 h	/	2016 μg·h/mL	2084 μg·h/mL	/	/	1.98 h	1137 ng/mL	0.29 h	82.5 %

In Vivo

MGD-4 (3 mg/kg; oral administration (p.o.); qd; 18 days) inhibits tumor growth in a xenograft model established in 6-week-old BALB/c nude mice subcutaneously inoculated with 5 × 10⁶ NCI-H929 cells; on day 10 of administration, the TGI value reaches 66.5%, and the treatment simultaneously reduces the proportion of Ki67-positive cells and the protein levels of IKZF1, IKZF2, and IKZF3 in tumor tissues^[1].
MGD-4 (10 mg/kg; oral administration (p.o.); qd; 18 days) achieves 92.8% TGI on day 10 of administration in the NCI-H929 xenograft tumor model; by day 18, it simultaneously reduces the proportion of Ki67-positive cells and the levels of IKZF1, IKZF2 and IKZF3 proteins in tumor tissues, exerts only a weak effect on CK1α protein levels, and is accompanied by only slight body weight loss^[1].
Combined oral administration of MGD-4 (3 mg/kg) and Dexamethasone (HY-14648) (3 mg/kg) once daily for 14 days achieves 90.21% TGI on day 10 in the NCI-H929 xenograft tumor model, while Dexamethasone administered alone yields a TGI of 43.7%; the antitumor effect of the co-administration regimen is maintained throughout the treatment period, further reduces Ki67-positive tumor cells, and no significant body weight loss or other identifiable toxic manifestations are observed^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model:

BALB/c nude mice (six-week-old; subcutaneous injection of NCI-H929 cells)^[1]
Dosage:

3 mg/kg
Administration:

p.o.; daily; 18 days
Result:

Produced a TGI of 66.5% after 10 days.
Reduced the percentage of Ki67-positive tumor cells.
Reduced tumor IKZF1 protein levels.
Reduced tumor IKZF2 protein levels.
Reduced tumor IKZF3 protein levels.
Showed minimal reduction of tumor CK1α protein.

Animal Model:

BALB/c nude mice (six-week-old; subcutaneous injection of NCI-H929 cells)^[1]
Dosage:

3 mg/kg
Administration:

p.o.; daily; 14 days
Result:

Produced a TGI of 92.8% after 10 days.
Exceeded the 80.1% TGI produced by pomalidomide at 10 mg/kg.
Reduced tumor volume to approximately half that of the 10 mg/kg pomalidomide group by day 18.
Reduced the percentage of Ki67-positive tumor cells.
Reduced tumor IKZF1 protein levels.
Reduced tumor IKZF2 protein levels.
Reduced tumor IKZF3 protein levels.
Showed minimal reduction of tumor CK1α protein.
Produced only slight body-weight loss during administration.

Animal Model:

BALB/c nude mice (six-week-old; subcutaneous injection of NCI-H929 cells)^[1]
Dosage:

MGD-4 3 mg/kg + Dexamethasone 3 mg/kg
Administration:

p.o.; once daily; 14 days
Result:

Produced a TGI of 90.21% on day 10.
Exceeded the 43.7% TGI produced by dexamethasone alone.
Maintained pronounced tumor-growth inhibition throughout continuous administration.
Reduced Ki67-positive tumor cells more strongly than single-agent administration.
Produced no discernible body-weight loss.
Produced no other discernible toxicity signs at the administered doses.

Chemical Information

No. CAS 2991817-99-1
Appearance Solid
Peso molecular 288.30
Fòrmula C₁₄H₁₆N₄O₃
Color Off-white to light yellow
SMILES

O=C1N(C2C(NC(CC2)=O)=O)N(C)CC3=C(N)C=CC=C31
Envío

Room temperature in continental US; may vary elsewhere.
Almacenamiento

4°C, protect from light

* In solvent : -80°C, 6 months; -20°C, 1 month (protect from light)

Pureza y Documentación

Select Batch:

Pureza: 99.98%

Assay: 99.98%

ee.: 99.98%

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COA (2659 KB)
Elemental Analysis Report (2659 KB)
HNMR (2659 KB)
CNMR (2659 KB)
RP-HPLC (2659 KB)
NP-HPLC (2659 KB)
MS (2659 KB)
LCMS (2659 KB)
IR (2659 KB)
GC (2659 KB)
OR (2659 KB)
SDS-PAGE (2659 KB)
SEC-HPLC (2659 KB)
Other Report (2659 KB)
Instrucciones de manejo (2659 KB)

Referencias

[1]. Li P, et al. Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation. Journal of hematology & oncology. 2024 Sep 02;17(1):77. [Content Brief]

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MGD-4

Ver todos los productos específicos de isoformas IKZF Family