MRTX1133 是一种非共价、有效和选择性的 KRAS G12D 抑制剂。 MRTX1133 以最佳方式填充开关 II 口袋并延伸三个取代基以有利地与蛋白质相互作用，导致对 KRAS G12D 的估计 KD 为 0.2 pM。 MRTX1133 阻止 SOS1 催化的核苷酸交换和/或 KRAS G12D/GTP/RAF1 复合物的形成，从而抑制突变的 KRAS 依赖性信号转导。 MRTX1133 选择性抑制 KRAS G12D 突变体，但不抑制 KRAS 野生型肿瘤细胞。 MRTX1133 在细胞试验中具有个位数的纳摩尔活性，并且在含有 KRAS G12D 突变的肿瘤模型中具有显着的体内功效。
货号:ajcx34240
CAS:2621928-55-8
分子式:C33H31F3N6O2
分子量：600.63
溶解度:N/A
纯度：98%
存储：Store at -20°C
库存：现货

Background:

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 IC₅₀of 2 nM. In the meanwhile, MRTX1133 was against the same cell line with an IC₅₀of 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 IC₅₀value 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]

参考文献:
[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.?