ZJK-807
ZJK-807 is a highly efficient and selective KRASG12D PROTAC degrader (DC50 = 79.5 nM in AsPC-1 cells). ZJK-807 promotes KRASG12D ubiquitination and degradation. ZJK-807 suppresses RAS/MAPK signaling and uniquely modulates TNF signaling and eukaryotic ribosome biogenesis. ZJK-807 can be used for the study of KRAS-driven pancreatic cancer.
(Pink: ligand (HY-W087383); Blue: Cereblon E3 ligase ligand; Black: linker).
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- Formule: C50H48F2N10O5
- Masse moléculaire:906.98
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Stockage:
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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Activité biologique
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Chemical Information
- Pureté et documentation
- Références
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Activité biologique
Description
IC50 & Target
[1]|
KRas G12D 79.5 nM (DC50) |
Cereblon |
In Vitro
ZJK-807 (Compound A11) (10 μM, 0.5-24 h) results in a time-dependent reduction in KRASG12D levels and a significant decrease in pERK levels, and can continue to degrade even after it has been removed in AsPC-1 cells[1].
ZJK-807 (1-3 μM, 12-16 h), at 1 μM for 16 hours, promotes the strong recruitment of HA-KRASG12D to CRBN E3 ligase in AsPC-1 cells, proving the formation of ternary complexes, and at 3 μM for 12 hours, it significantly enhances the polyubiquitination of KRASG12D in the same cell line[1].
ZJK-807 (0.1-3 μM, 24 h) induces significant, concentration-dependent degradation of KRAS protein in AsPC-1 (KRASG12D) cells, and shows no appreciable degradation of KRAS protein was observed in other KRAS mutant cell lines[1].
ZJK-807 (1.5-10000 nM, 24 h) exhibits potent and concentration-dependent degradation of KRASG12D with DC50 values of 79.5 nM (DMAX 92%) in AsPC-1 cells, 130.8 nM (DMAX 92%) in GP2D cells, and 313.8 nM (DMAX 70%) in AGS cells, while it does not induce concentration-dependent degradation of CK1α or GSPT1 in AsPC-1 and GP2D cells[1].
ZJK-807 (3 or 5 days) exhibits antiproliferative effects on KRASG12D mutant cell lines, with IC50 values of 219.6 nM in AsPC-1, 273.5 nM in AGS, and 1110 nM in GP2D cells, and shows no substantial antiproliferative activity was observed in cell lines with wild-type or other KRAS mutations or on the normal cell line HEK-293T[1].
ZJK-807 (0.01-10 μM, 24 h) can reduce KRASG12D protein levels in a concentration-dependent manner in AGS cells even in the presence of secondary mutations, and although its inhibitory efficacy is reduced, it still inhibits Ba/F3 cells carrying KRASG12D/95mut or KRASG12D/96mut [1].
ZJK-807 significantly alters the transcriptome with notable down-regulation and pathway enrichment in RAS/MAPK signaling[1].
ZJK-807, a KRASG12D-selective degrader, attenuates RAS-MAPK signaling and reduces growth in PDAC cells while sparing wild-type RAS[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:AsPC-1 cells
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Concentration:10 μM
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Incubation Time:0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h
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Result:Resulted in a time-dependent reduction in KRASG12D levels and a significant decrease in pERK levels, observed as early as 2 h post-treatment, indicating sustained downregulation of the ERK pathway for up to 24 h in AsPC-1 cells.
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Cell Line:AsPC-1 cells
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Concentration:3 μM
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Incubation Time:12 h
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Result:KRASG12D degradation was significantly alleviated by the competitive binding of MRTX1133 (1 μM) and thalidomide (40 μM).
Pretreatment with the NEDD8-activating E1 enzyme inhibitor MLN4924 (1 μM) or the proteasome inhibitor MG132 (3 μM) for 4 h effectively attenuated the degradation of KRASG12D protein in AsPC-1 cells.
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Cell Line:AGS cells
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Concentration:0.01 μM, 0.1 μM, 1 μM, 10 μM
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Incubation Time:24 h
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Result:Reduced KRASG12D protein levels in a concentration-dependent manner, even in the presence of secondary mutations in AGS cells.
Parmacokinetics
| Species | Dose | Route | T1/2 | Tmax | Cmax | AUClast | MRTINF_obs |
|---|---|---|---|---|---|---|---|
| Mice | 30 mg/kg | i.p. | 1.67 h | 0.5 h | 7086 ng/mL | 26103 ng·h/mL | 4.92 h |
| Mice | 30 mg/kg | s.c. | 7.43 h | 0.33 h | 9869 ng/mL | 26346 ng·h/mL | 6.08 h |
In Vivo
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:5.0 × 106 AsPC-1 cells suspended in 100 μL of PBS and Matrigel were subcutaneously implanted into the right flank of male BALB/c nude mice[1].
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Dosage:30 mg/kg
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Administration:S.c., once daily for 28 days
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Result:Tumor growth was significantly inhibited with a 47% reduction in tumor volume compared to the Vehicle group.
No significant decrease in body weight was observed.
The tumor weight was significantly lower than that in the Vehicle group.
KRASG12D protein expression level was significantly reduced.
Chemical Information
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Masse moléculaire 906.98
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Formule C50H48F2N10O5
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SMILES
O=C1N(C(CC2)C(NC2=O)=O)C(C3=C1C=CC(N4CC5(CCC(N(C6CN(C7=NC(N8C[C@@](N9)([H])CC[C@@]9([H])C8)=C(C=NC(C%10=C%11C(C#C)=C(F)C=CC%11=CC(O)=C%10)=C%12F)C%12=N7)C6)C)CC5)C4)=C3)=O
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
ZJK-807 Related Classifications
HY-178497 Related Classifications
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