2. GPCR/G Protein MAPK/ERK Pathway Apoptosis
  3. Ras Apoptosis p38 MAPK Caspase TNF Receptor
  4. 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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MCB-294

MCB-294 Chemical Structure

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MCB-294 Related Antibodies

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Description

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[1].

IC50 & Target[1]

KRas G12C

 

KRas G12D

 

KRas G12V

 

KRAS G13D

 

K-Ras WT

 

Caspase 3

 

In Vitro

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.

MCB-294 Related Antibodies

Western Blot Analysis[1]

Cell Line: AsPC-1 and H358 cells
Concentration: 0, 10, 30 and 100 nM
Incubation Time: 0, 3, 6, 12, 24 h
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.

Western Blot Analysis[1]

Cell Line: MIA PaCa-2 (G12C), MIA PaCa-2 (G12C/Y96C) and MIA PaCa-2 (G12C/H95D)
Concentration: 30 nM
Incubation Time: 0, 1, 3, 6, 12, 24, 36, 48, 72 h
Result: Inhibited p-ERK levels, induced cell death and retained their potency over at least 36 h.
In Vivo

MCB-36 (10 mg/kg, i.p., single dose) achieves rapid systemic exposure, reaching peak plasma concentration at 0.5 h post-dosing with a plasma elimination half-life (t1/2) of 1.1 h[1].
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.

Animal Model: AsPC-1/H358 induced xenograft model established in six- to eight-week-old male BALB/c nude mice[1]
Dosage: 30 mg/kg
Administration: Intraperitoneal administration (i.p.), twice daily, for 1 or 7 days
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.
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]
Dosage: 30 mg/kg
Administration: Intraperitoneal administration (i.p.), twice daily, for 16 days
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.
Animal Model: CT26 induced immunoregulation model established in six- to eight-week-old male BALB/c nude mice[1]
Dosage: 30 mg/kg
Administration: Intraperitoneal administration (i.p.), twice daily, for 2 days
Result: Increased the abundance of effector CD8+ T cells, IFN-γ, TNF-α and Ki67.
Enhanced the efficacy of anti-PD-1 therapy.
Molecular Weight

635.65

Formula

C34H29D2F4N5O3
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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Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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MCB-294 Related Classifications

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Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

MCB-294MCB294MCB 294RasApoptosisp38 MAPKCaspaseTNF ReceptorTumor Necrosis Factor ReceptorTNFRKRAS signalingcancer therapeuticsdegraderimmune evasiononcogenic KRASpan-KRAS inhibitortargeted protein degradationtherapy resistancetumor immune microenvironmentInhibitorinhibitorinhibit

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