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]。