MCB-294
MCB-294 is a dual-state pan-KRAS inhibitor that selectively inhibits KRAS over NRAS and HRAS. MCB-294 capable of binding both the active (GTP-bound) and inactive (GDP-bound) forms of KRAS with Kds of approximately 1 pM and 10 nM, respectively. MCB-294 broadly impairs the growth of hTERT-HPNE cells expressing G12D, G12C, G12V, G12S, G13D, and wild-type KRAS, with IC50s of approximately 700 nM. MCB-294 induces irreversible apoptosis in KRAS-mutated tumors. MCB-294 effectively suppress KRASG12C inhibitor-resistant cancer cells and remodel the tumor immune microenvironment. MCB-294 can be used for the study of pancreatic cancer, colorectal cancer and lung cancer.
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- Formule: C34H29D2F4N5O3
- Masse moléculaire:635.65
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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
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KRas G12C |
KRas G12D |
KRas G12V |
KRAS G13D |
K-Ras WT |
Caspase 3 |
MCB-294 inhibits the binding of SOScat to KRAS proteins and disrupted RAF-RBD peptide binding to active KRAS with IC50 values approximately ranging from 1 to 70 nM and from 20 to 150 nM[1].
MCB-294 (1 nM-100 μM, 5 days) shows significant anti-proliferative effects on KRAS-dependent cancer cells that rely on KRAS (as PC-1 (G12D), H358 (G12C), LS180 (G12V), HCT116 (G13D), etc.) for growth and survival (24 of 30 cell lines tested with a mean IC50 of around 125 nM) while sparing normal cells (hTERT-HPNE, NCM460) (IC50 > 10 μM)[1].
MCB-294 (0-100 nM, 0-72 h) causes a dose-dependent reduction in p-ERK levels, persistently inhibits components of the MAPK signaling pathway (p-ERK, DUSP6, and cyclin D1) and induces apoptosis markers (CC3 and cPARP) in AsPC-1 and H358 tumors in all tested KRAS-dependent cancer cells including MIA PaCa-2 cells expressing KRASG12C, KRASG12C/Y96C, and KRASG12C/H95D[1].
MCB-294 downregulates pro-survival genes (BIRC5, MCL1, and BCL2L1), upregulates pro-apoptotic genes (BBC3, BCL2L11, and BMF) and decreases KRAS-regulated genes such as CCND1, DUSP6, ETV4, SPRY2, and PHLDA1[1].
MCB-294 significantly upregulates the interferon-alpha response pathway in CD45+ immune cells isolated from CT26 tumors and increases the abundance of effector CD8+ T cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:AsPC-1 and H358 cells
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Concentration:0, 10, 30 and 100 nM
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Incubation Time:0, 3, 6, 12, 24 h
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Result:Induced apoptosis markers (CC3 and cPARP) as early as 6 h post-treatment, with effects sustained for 24 h in KRAS-dependent cancer cells.
Preferentially traped KRAS in an inactive state.
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Cell Line:MIA PaCa-2 (G12C), MIA PaCa-2 (G12C/Y96C) and MIA PaCa-2 (G12C/H95D)
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Concentration:30 nM
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Incubation Time:0, 1, 3, 6, 12, 24, 36, 48, 72 h
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Result:Inhibited p-ERK levels, induced cell death and retained their potency over at least 36 h.
MCB-294 (30 mg/kg, i.p., twice daily for 1-16 days) effectively suppresses KRASG12C inhibitor-resistant cancer cells and remodel the tumor immune microenvironment in mice[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:AsPC-1/H358 induced xenograft model established in six- to eight-week-old male BALB/c nude mice[1]
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Dosage:30 mg/kg
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Administration:Intraperitoneal administration (i.p.), twice daily, for 1 or 7 days
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Result:Observed p-ERK levels accompanied by reduced plasma drug concentration at 6 h post-treatment under the 1-day dosing regimen, sustained p-ERK suppression was achieved with continuous 7-day dosing.
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Animal Model:Patient-derived xenograft (PDX) model induced by pancreatic ductal adenocarcinoma harboring a KRASG12D mutation (PDX A01), colorectal carcinoma harboring a KRASG12C mutation (PDX A02), and lung adenocarcinoma harboring a KRASG12V mutation (PDX A03) established in four- to five-week-old male BALB/c mice[1]
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Dosage:30 mg/kg
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Administration:Intraperitoneal administration (i.p.), twice daily, for 16 days
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Result:Inhibited tumor growth and maintained the inhibitory effect even after discontinuation of the medication.
Decreased p-ERK and Ki67 levels and increased caspase 3 activity.
No abnormalities in the heart, liver, spleen, lungs, or kidneys and significant weight loss.
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Animal Model:CT26 induced immunoregulation model established in six- to eight-week-old male BALB/c nude mice[1]
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Dosage:30 mg/kg
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Administration:Intraperitoneal administration (i.p.), twice daily, for 2 days
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Result:Increased the abundance of effector CD8+ T cells, IFN-γ, TNF-α and Ki67.
Enhanced the efficacy of anti-PD-1 therapy.
1. This compound can be used as a tracer
2. This compound can be used as an internal standard for quantitative analysis by NMR, GC-MS, or LC-MS.
Chemical Information
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Masse moléculaire 635.65
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Formule C34H29D2F4N5O3
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SMILES
O[C@](C1)(C)CCCN1C2=NC(OC([2H])([2H])C3(CCC4)N4C/C(C3)=C(F)/F)=NC5=C(F)C(C6=C(C(C#C)=C(F)C=C7)C7=CC(O)=C6)=NC=C52
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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)
MCB-294 Related Classifications
HY-176785S Related Classifications
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