MRTX849
(Synonyms: (2S)-4-[7-(8-氯-1-萘)-5,6,7,8-四氢-2-[[((2S)-1-甲基-2-吡咯烷基]甲氧基]吡啶基[3,4-d]嘧啶-4-基]-1-(2-氟-1-氧代-2-丙烯-1-基)-2-哌嗪乙腈,MRTX849) 目录号 : GC38400
MRTX849 (Adagrasib)是一种KRASG12C的高效、选择性共价抑制剂,IC50值为5nM。
Cas No.:2326521-71-3
Sample solution is provided at 25 µL, 10mM.
MRTX849 (Adagrasib) is a highly potent and selective covalent inhibitor of KRASG12C, with an IC50 value of 5nM[1]. MRTX849 specifically targets and irreversibly modifies the mutant cysteine 12 residue in the GDP-bound state of KRASG12C, thereby effectively suppressing KRAS-dependent signaling pathways[2]. MRTX849 is specifically designed to exhibit optimal characteristics as a KRASG12C inhibitor, incorporating advantageous pharmacokinetic features such as high oral bioavailability, an extended half-life of approximately 24 hours, dose-dependent pharmacokinetic behavior, and broad tissue distribution[1, 3].
In vitro, MRTX849 has potent anti-proliferative activity across a broad spectrum of KRASG12C-mutant cell lines (MIA PaCa-2 cells, NCI-H1373 cells, NCI-H358 cells, NCI-H2122 cells, SW1673 cells, NCI-H2030 cells, KYSE-410 cells, H1299 cells, A549 cells and HCT116 cells), exhibiting IC50 values ranging from 10 to 973nM in monolayer culture cells (3-48 hours) and from 0.2 to 1042nM in three-dimensional spheroid models (48 hours)[2]. MRTX849 effectively suppresses KRAS-dependent signaling pathways, including the phosphorylation of ERK1/2 (Thr202/Tyr204; pERK), phosphorylation of S6 (RSK-dependent Ser235/236; pS6), and the expression of the ERK-regulated gene DUSP6, with IC50 values consistently in the single-digit nanomolar range within H358 and MIA PaCa-2 cell lines[2]. MRTX849 effectively counteracts ATP-binding cassette subfamily B member 1 (ABCB1)-mediated multidrug resistance (MDR) in vitro by selectively inhibiting the efflux activity of ABCB1 in drug-resistant cancer cells[4].
A single oral dose of MRTX849 (100mg/kg) reduced intratumoral myeloid-derived suppressor cells while enhancing the infiltration of M1-polarized macrophages, dendritic cells, and CD4+ and CD8+ T cells in a KrasG12C-mutant CT26 syngeneic mouse model[5]. Within immune-competent BALB/c mice bearing CT26 KrasG12C E3 cell xenografts, daily oral administration of 30mg/kg/day achieved significant tumor growth inhibition, and 100mg/kg MRTX849 treatment resulted in complete tumor regression[5]. In C57B/6J mice bearing mKRC.1 cell xenografts, the combination of MRTX849 (30mg/kg, administered daily via oral gavage) and RMC-4550 (30mg/kg, administered daily via oral gavage) induced significant tumor regression and markedly improved survival. This combined treatment resulted in sustained tumor reduction to less than 10% of the initial tumor volume[6].
References:
[1] Sabari J K, Velcheti V, Shimizu K, et al. Activity of adagrasib (MRTX849) in brain metastases: preclinical models and clinical data from patients with KRASG12C-mutant non-small cell lung cancer[J]. Clinical Cancer Research, 2022, 28(15): 3318-3328.
[2] Hallin J, Engstrom L D, Hargis L, et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients[J]. Cancer discovery, 2020, 10(1): 54-71.
[3] Fell J B, Fischer J P, Baer B R, et al. Identification of the clinical development candidate MRTX849, a covalent KRASG12C inhibitor for the treatment of cancer[J]. Journal of medicinal chemistry, 2020, 63(13): 6679-6693.
[4] Zhang Y, Li C, Xia C, et al. Adagrasib, a KRAS G12C inhibitor, reverses the multidrug resistance mediated by ABCB1 in vitro and in vivo[J]. Cell Communication and Signaling, 2022, 20(1): 142.
[5] Briere D M, Li S, Calinisan A, et al. The KRASG12C inhibitor MRTX849 reconditions the tumor immune microenvironment and sensitizes tumors to checkpoint inhibitor therapy[J]. Molecular cancer therapeutics, 2021, 20(6): 975-985.
[6] Sisler D J, Hinz T K, Le A T, et al. Evaluation of KRASG12C inhibitor responses in novel murine KRASG12C lung cancer cell line models[J]. Frontiers in oncology, 2023, 13: 1094123.
MRTX849 (Adagrasib)是一种KRASG12C的高效、选择性共价抑制剂,IC50值为5nM[1]。MRTX849特异性靶向并不可逆地修饰KRASG12C与GDP结合状态下的突变半胱氨酸12残基,从而有效抑制KRAS依赖的信号通路[2]。MRTX849被专门设计为表现出KRASG12C抑制剂的最佳特性,包括优势的药代动力学特征,如高口服生物利用度、约24小时的半衰期、剂量依赖性药代动力学特质和广泛的组织分布[1,3]。
在体外,MRTX849在多种KRASG12C突变细胞系(包括MIA PaCa-2细胞、H1373细胞、H358细胞、H2122细胞、SW1673细胞、H2030细胞、KYSE-410细胞、H1299细胞、A549细胞和HCT116细胞)中表现出显著的抗增殖活性。在单层培养细胞中(3-48小时),MRTX849的IC50值范围为10-973nM;在三维球体模型中(48小时),IC50值范围为0.2-1042nM[2]。在H358和MIA PaCa-2细胞系中(MRTX849的IC50值始终保持在个位数纳摩尔范围内),MRTX849能够有效抑制KRAS依赖性信号通路,包括ERK1/2的磷酸化(Thr202/Tyr204;pERK)、S6的磷酸化(RSK依赖性Ser235/236;pS6)以及 ERK 调控基因DUSP6的表达[2]。此外,MRTX849通过选择性抑制ABCB1(ATP结合盒亚家族B成员1)的外排活性,有效克服了ABCB1介导的多药耐药性(MDR)[4]。
单次口服MRTX849(100mg/kg)在KRASG12C突变的CT26同源小鼠模型中减少了肿瘤内髓系来源抑制性细胞(MDSC)的数量,同时增加了M1型极化巨噬细胞、树突状细胞以及CD4+和CD8+T细胞的浸润[5]。在携带CT26 KrasG12CE3细胞异种移植瘤且具有免疫能力的BALB/c小鼠中,每日口服30mg/kg剂量的MRTX849能显著抑制肿瘤生长,每日口服100mg/kg的MRTX849则实现了肿瘤的完全消退[5]。在携带mKRC.1细胞异种移植瘤的C57B/6J小鼠中,联合使用MRTX849(30mg/kg,每日口服灌胃)和RMC-4550(30mg/kg,每日口服灌胃)显著诱导了肿瘤消退并明显提高了动物模型的生存率,该联合治疗使肿瘤体积持续缩小至初始体积的10%以下[6]。
Cell experiment [1]: | |
Cell lines | CT26.WT cell; CT26 KrasG12C E3 clone cells |
Preparation Method | The CT26.WT cell line was genetically modified using CRISPR/Cas9 to substitute the endogenous KrasG12D alleles with KrasG12C. The engineered CT26 KrasG12C E3 clone cells were seeded in 96-well white-walled plates under standard tissue culture conditions to assess cell viability. Then, cells were exposed to varying concentrations of MRTX849 (1, 100, and 10,000μM). Initial viable cell counts were determined using Trypan Blue exclusion to ensure consistent cell numbers per well at the start of the experiment. A Cell Titer-Glo viability assay was conducted on both parental and CT26 KrasG12C E3 clone cells following in vitro treatment with MRTX849 for 6, 12, 24, 48 and 72h. |
Reaction Conditions | 1, 100 and 10000μM; 6, 12, 24, 48 and 72h |
Applications | MRTX849 significantly inhibited the viability of CT26 KrasG12C E3 clone cells in a time- and dose-dependent manner. |
Animal experiment [2]: | |
Animal models | NOD scid mice |
Preparation Method | Female NOD scid mice, aged 6-8 weeks, were shaved before injection, and 100μL of the SW1573 cell suspension was subcutaneously administered into the rear flank using a pre-chilled 26 7/8-gauge syringe. Mice were randomized, and treatment commenced when the average tumor volume reached approximately 250-300mm3. The animals were divided into two groups (n=5 per group): one receiving vehicle control (10% Captisol in 10mM citrate buffer, pH 5.0) and the other administered 100mg/kg MRTX849 daily via oral gavage for 21 days. |
Dosage form | 100mg/kg/day for 21 days; p.o. |
Applications | MRTX849 treatment significantly suppressed tumor growth, downregulated E2F1 and specific E2F family target genes, and upregulated p27 protein expression more effectively than either single agent alone, while markedly reducing the population of Ki67-positive cells. |
References: |
Cas No. | 2326521-71-3 | SDF | |
别名 | (2S)-4-[7-(8-氯-1-萘)-5,6,7,8-四氢-2-[[((2S)-1-甲基-2-吡咯烷基]甲氧基]吡啶基[3,4-d]嘧啶-4-基]-1-(2-氟-1-氧代-2-丙烯-1-基)-2-哌嗪乙腈,MRTX849 | ||
Canonical SMILES | N#CC[C@@H]1N(C(C(F)=C)=O)CCN(C2=C3C(CN(C4=C5C(Cl)=CC=CC5=CC=C4)CC3)=NC(OC[C@H]6N(C)CCC6)=N2)C1 | ||
分子式 | C32H35ClFN7O2 | 分子量 | 604.12 |
溶解度 | DMSO: 25 mg/mL (41.38 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
1 mM | 1.6553 mL | 8.2765 mL | 16.553 mL |
5 mM | 0.3311 mL | 1.6553 mL | 3.3106 mL |
10 mM | 0.1655 mL | 0.8277 mL | 1.6553 mL |
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