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.