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

MCB-294 是一种双态泛 KRAS 抑制剂，对KRAS 的选择性高于 NRAS 和 HRAS。MCB-294能够结合活性 (GTP 结合) 和非活性 (GDP 结合) 形式的 KRAS，其 Kd 值约为 1 pM 和 10 nM。MCB-294 广泛抑制表达 G12D、G12C、G12V、G12S、G13D 和野生型 KRAS 的 hTERT-HPNE 细胞的生长，IC50 值约 700 nM。MCB-294在 KRAS 突变肿瘤中诱导不可逆的凋亡 (apoptosis)。MCB-294 有效抑制 KRASG12C< sup>耐药癌细胞，重塑肿瘤免疫微环境。MCB-294 可用于胰腺癌、结直肠癌和肺癌的研究。

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MCB-294

MCB-294 Chemical Structure

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MCB-294 相关抗体

Top Publications Citing Use of Products

查看 Ras 亚型特异性产品:

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K-Ras H-Ras N-Ras Ras

查看 p38 MAPK 亚型特异性产品:

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p38 MAPK p38α p38β MAPK13 p38δ p38γ

查看 Caspase 亚型特异性产品:

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Caspase 1 Caspase 2 Caspase 3 Caspase 4 Caspase 5 Caspase 6 Caspase 7 Caspase 8 Caspase 9 Caspase 10 Caspase 12 Caspase Caspase 11 Caspase-13

查看 TNF Receptor 亚型特异性产品:

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TNFRSF1A/CD120a TNFRSF4 TNFRSF5/CD40 TNFRSF6/Fas/CD95 TNFRSF7/CD27 TNFRSF8/CD30 TNFRSF9/4-1BB/CD137 TNFRSF12A/TWEAK TNFRSF16/NGF Receptor/CD271 TNFRSF18/GITR/CD357

  • 生物活性

  • 纯度 & 产品资料

  • 参考文献

生物活性

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

 

体外研究
(In Vitro)

MCB-294 能够抑制 SOScat 与 KRAS 蛋白的结合，并破坏 RAF-RBD 肽与活性 KRAS 的结合，其 IC50 值大致在 1 至 70 nM 以及 20 至 150 nM 之间[1]。
MCB-294 (1 nM-100 μM, 5 days) 对 KRAS 依赖性癌细胞 (如PC-1 (G12D)、H358 (G12C)、LS180 (G12V)、HCT116 (G13D) 等) 显示出显著的抗增殖作用 (测试的 30 个细胞系中有 24 个平均 IC50约为125 nM)，同时对正常细胞 (hTERT-HPNE、NCM460) 无明显影响 (IC50 > 10 μM)[1]。
MCB-294 (0-100 nM, 0-72 h) 在所有测试的 KRAS 依赖性癌细胞中引起 p-ERK 水平的剂量依赖性降低，持续抑制 MAPK 信号通路的组分 (p-ERK、DUSP6 和 cyclin D1) 并上调凋亡标志物 (CC3 和 cPARP), 包括表达 KRASG12C、KRASG12C/Y96C 和 KRASG12C/H95D的 MIA PaCa-2 细胞[1]。
MCB-294 在 AsPC-1 和 H358 肿瘤中下调促存活基因 (BIRC5、MCL1和BCL2L1) ，上调促凋亡基因 (BBC3、BCL2L11和BMF) ，并降低 KRAS 调控的基因如 CCND1、DUSP6、ETV4、SPRY2 和 PHLDA1[1]。
MCB-294 显著上调从 CT26 肿瘤中分离的 CD45+免疫细胞中的 TNF-α 应答通路，并增加效应性 CD8+ T 细胞的丰度[1]。

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

MCB-294 相关抗体:

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.
体内研究
(In Vivo)

MCB-294 (10 mg/kg, i.p., 单次给药) 实现快速全身暴露，在给药后 0.5 小时达到血浆浓度峰值，血浆消除半衰期 (t1/2) 为 1.1 小时[1]。
MCB-294 (30 mg/kg, i.p., 每日 2 次, 共 1-16 天) 有效抑制 KRASG12C 耐药的癌细胞，并重塑小鼠的肿瘤免疫微环境[1]。

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.
分子量

635.65

Formula

C34H29D2F4N5O3
运输条件

Room temperature in continental US; may vary elsewhere.
储存方式

Please store the product under the recommended conditions in the Certificate of Analysis.
纯度 & 产品资料
参考文献

MCB-294 相关分类

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  • 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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