MRTX1133 is an exceptionally potent and selective KRASG12D inhibitor with high affinity (<2nM).[1]
In vitro, in the AGS cell line, MRTX1133 inhibited ERK phosphorylation with an IC50 of 2 nM. In the meanwhile, MRTX1133 was against the same cell line with an IC50 of 6 nM in a 2D viability assay.[1] In vitro efficacy test, in KRASG12D–mutant HPAC Cells, it indicated that treatment with 0.05 nM - 300 nM MRTX1133 has a dose-dependent pERK, pS6 & DUSP6 modulation.[2]
In vivo experiment it shown that treatment with 30 mg/kg of MRTX1133 intraperitoneally in CD-1 mice caused the sustained plasma exposure exceeding the free-fraction-adjusted pERK IC50 value in the KRASG12D mutant Panc 04.03 cell line for approximately 8 h. And in the Panc 04.03 xenograft tumor model, it suggested that MRTX1133 (3-30 mg/kg, i.p.) has dose-dependent antitumor activity with 94% growth inhibition observed at 3 mg/kg BID (IP) and tumor regressions of ?62% and ?73% observed at 10 and 30 mg/kg BID (IP), respectively.[1]
References:
[1].Wang X, Allen S, et al. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D?Inhibitor. J Med Chem. 2022 Feb 24;65(4):3123-3133.
[2].Swiatnicki M, Engel L, Shrestha R, Alves J, Goueli SA, Zegzouti H. Profiling oncogenic KRAS mutant drugs with a cell-based Lumit p-ERK immunoassay. SLAS Discov. 2022 Jun;27(4):249-257.?
MRTX1133 是一种非常有效的选择性 KRASG12D 抑制剂，具有高亲和力 (<2nM)。[1]
在体外，在 AGS 细胞系中，MRTX1133 抑制 ERK 磷酸化，IC50 为 2 nM。同时，MRTX1133 在 2D 活力测定中针对同一细胞系，IC50 为 6 nM。[1] 体外药效测试，在 KRASG12D-突变体中HPAC 细胞，它表明用 0.05 nM - 300 nM MRTX1133 处理具有剂量依赖性 pERK，pS6 &； DUSP6 调制。[2]
体内实验表明，在 CD-1 小鼠中用 30 mg/kg 的 MRTX1133 进行腹膜内处理会导致持续的血浆暴露超过 KRASG12D 突变体中自由分数调整的 pERK IC50 值Panc 04.03 细胞系约 8 小时。在 Panc 04.03 异种移植肿瘤模型中，它表明 MRTX1133（3-30 mg/kg，i.p.）具有剂量依赖性抗肿瘤活性，在 3 mg/kg BID (IP) 时观察到 94% 的生长抑制和 -62 的肿瘤消退% 和 -73% 分别在 10 和 30 mg/kg BID (IP) 下观察到。[1]