CH091138
CH091138 is an orally active VHL-recruiting PROTAC degrader targeting KRASG12D, with a DC50 of 148.3 nM in HeLa cells. CH091138 inhibits cancer cell proliferation and tumor growth by mediating the ubiquitin-proteasome degradation of KRASG12D. CH091138 can be used in research related to pancreatic cancer and colorectal cancer.
(Pink: KRas G12D ligand (HY-175144); Blue: VHL ligand (HY-138678); Black: linker).
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- Formule: C59H69FN10O6S
- Masse moléculaire:1065.31
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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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Activité biologique
Description
IC50 & Target
[1]|
KRas G12D 148.3 nM (DC50) |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| HeLa | DC50 |
148.3 nM
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KRASG12D degradation activity in HeLa cells stably expressing KRASG12D-eGFP assessed by FACS or Western blot analysis after 24 h treatment.
KRASG12D degradation activity in HeLa cells stably expressing KRASG12D-eGFP assessed by FACS or Western blot analysis after 24 h treatment.
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40651134 |
| ASPC1 | DC50 |
469.8 nM
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Endogenous KRASG12D degradation activity in AsPC-1 cells assessed by Western blot analysis after 24 h treatment.
Endogenous KRASG12D degradation activity in AsPC-1 cells assessed by Western blot analysis after 24 h treatment.
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40651134 |
| ASPC1 | GI50 |
0.75 μM
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Antiproliferative activity against human AsPC-1 (KRASG12D) cells assessed as reduction in cell viability after 72 h treatment.
Antiproliferative activity against human AsPC-1 (KRASG12D) cells assessed as reduction in cell viability after 72 h treatment.
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40651134 |
| AGS | GI50 |
1.80 μM
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Antiproliferative activity against human AGS (KRASG12D) cells assessed as reduction in cell viability after 72 h treatment.
Antiproliferative activity against human AGS (KRASG12D) cells assessed as reduction in cell viability after 72 h treatment.
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40651134 |
| BaF3 | GI50 |
4.75 μM
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Antiproliferative activity against KRASG12D BaF3 cells assessed as reduction in cell viability after 72 h treatment.
Antiproliferative activity against KRASG12D BaF3 cells assessed as reduction in cell viability after 72 h treatment.
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40651134 |
In Vitro
CH091138 (1-30 μM; 24 h) reduces GFP signal in HeLa cells expressing KRASG12D-eGFP[1].
CH091138 (1-30 μM; 24 h) induces the degradation of KRAS in HeLa cells expressing KRASG12D-eGFP[1].
CH091138 (0.001-10 μM; 24 h) induces dose-dependent degradation of endogenous KRASG12D in AsPC-1 cells[1].
CH091138 (0.001-10 μM; 24 h) induces dose-dependent degradation of exogenous KRASG12D-eGFP and endogenous KRASWT in HeLa cells expressing KRASG12D-eGFP[1].
CH091138 (10-50 μM; 4 h) modulates MZ1-induced target binding in BRD4-eGFP-mCherry HeLa cells[1].
CH091138 (1-30 μM; 24 h) does not reduce KRAS mRNA levels in AsPC-1 cells[1].
CH091138 (1 μM; 30 min) retains 61.9% stability in mouse liver microsomes and 43.6% stability in human liver microsomes[1].
CH091138 (compound 6) (1 nM-10 μM; 24 h) efficiently degrades KRASG12D in HeLa cells stably expressing KRASG12D-eGFP, with a DC50 of 148.3 nM and a maximum degradation rate of 85%[1].
CH091138 (1 nM-10 μM; 4-24 h) potently and time-dependently degrades endogenous KRASG12D in AsPC-1 cells, with a DC50 of 469.8 nM and a maximum degradation rate of 89%[1].
CH091138 (1-30 μM; 24 h) degrades KRASG12D in SNU407 heterozygous KRASG12D/WT cells and KRASG12D-expressing BaF3 cells, with lower activity observed in BaF3 cells than in human cell lines[1].
CH091138 (1-30 μM; 24 h) selectively degrades KRASG12D in PC9, H358, A549, KRASG12C BaF3 and KRASG12V BaF3 cells, without degrading KRASWT or non-G12D KRAS mutants[1].
CH091138 (10 μM; 24 h) selectively downregulates intracellular KRAS protein in AsPC-1 cells[1].
CH091138 (1-30 μM; 24 h)-mediated degradation of KRASG12D in AsPC-1 cells relies on the VHL-mediated ubiquitin-proteasome system, requires binding to KRASG12D, and involves direct interaction with VHL[1].
CH091138 (1-10 μM; 4 h) directly binds to KRASG12D and induces the formation of a ternary complex between KRASG12D and VHL in HEK293T cells[1].
CH091138 (10-30 μM; 24 h) inhibits the downstream signaling pathway of KRAS in AsPC-1 cells[1].
CH091138 (72 h) selectively inhibits the viability of cells harboring KRASG12D (AsPC-1, AGS, SNU407, KRASG12D BaF3), with GI50 values ranging from 0.75 to 9.36 μM, but shows no significant activity against KRASWT cells or cells with non-G12D KRAS mutations[1].
CH091138 (1-30 μM; 24 h) inhibits migration and invasion of AsPC-1 cells in a dose-dependent manner[1].
CH091138 (1-10 μM) inhibits 2D colony formation of AsPC-1 cells, exhibits significant activity at a concentration of 1 μM, and reaches peak activity at 10 μM[1].
CH091138 (10 μM; 24-48 h) induces apoptosis in AsPC-1 cells, and higher activity is observed at 48 h compared with 24 h[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:KRAS^G12D-eGFP expressing HeLa cells
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Concentration:1 μM, 10 μM, 30 μM
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Incubation Time:24 h
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Result:Effectively induced degradation of KRAS protein at all tested concentrations.
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Cell Line:AsPC-1 cells
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Concentration:0.001 μM, 0.004 μM, 0.013 μM, 0.041 μM, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, 10 μM
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Incubation Time:24 h
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Result:Caused dose-dependent degradation of endogenous KRASG12D over the tested concentration range.
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Cell Line:KRAS^G12D-eGFP expressing HeLa cells
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Concentration:0.001 μM, 0.004 μM, 0.013 μM, 0.041 μM, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, 10 μM
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Incubation Time:24 h
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Result:Caused dose-dependent degradation of both exogenous KRASG12D-eGFP and endogenous KRASWT over the tested concentration range.
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Cell Line:AsPC-1 cells
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Concentration:1 μM, 10 μM, 30 μM
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Incubation Time:24 h
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Result:Did not reduce KRAS mRNA levels relative to control.
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Cell Line:AsPC-1 cells
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Concentration:10 μM, 30 μM
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Incubation Time:24 h
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Result:Reduced levels of pAKT, pMEK1/2, and pERK1/2 in AsPC-1 cells.
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Cell Line:AsPC-1 cells
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Concentration:10 μM
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Incubation Time:24 h, 48 h
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Result:Induced apoptosis in AsPC-1 cells, with a higher percentage of apoptotic cells observed after 48 h compared to 24 h.
Parmacokinetics
In Vivo
CH091138 (1-10 mg/kg; i.v., p.o.; single administration) exhibits a low oral bioavailability of 0.02% in mice, and is characterized by rapid clearance and short half-life following both intravenous and oral administration[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Balb/C nude mice (five-week-old female; subcutaneous xenograft of AsPC-1 cells harboring KRASG12D)[1]
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Dosage:60 mg/kg
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Administration:i.p.; once every three days; 29 days
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Result:Achieved 61.8% tumor growth inhibition.
Reduced tumor KRAS protein levels by up to 76.04%.
Caused no significant body weight change.
Chemical Information
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Masse moléculaire 1065.31
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Formule C59H69FN10O6S
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SMILES
OC1=CC(C=CC=C2C#C)=C2C(C3=C(F)C(N=C(OC[C@@H]4CCCN4CCCCCCC(N[C@H](C(N5[C@H](C(NCC6=CC=C(C7=C(C)N=CS7)C=C6)=O)C[C@@H](O)C5)=O)C(C)(C)C)=O)N=C8N9C[C@H]%10N[C@H](CC%10)C9)=C8C=N3)=C1
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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)
CH091138 Related Classifications
HY-175025 Related Classifications
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