RMC-4550

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Chemical Structure| 2172651-73-7 同义名 : -
CAS号 : 2172651-73-7
货号 : A1001786
分子式 : C21H26Cl2N4O2
纯度 : 99%+
分子量 : 437.36
MDL号 : N/A
存储条件：

Pure form Keep in dark place, inert atmosphere, 2-8°C

In solvent -20°C:3-6个月-80°C:12个月
溶解度 : -
生物活性
描述 RMC-4550 is a potent, selective and allosteric inhibitor of SHP2 enzyme with IC50 value of 0.58 nM, without activity against the SHP2 catalytic domain up to a concentration of 10 µM. RMC-4550 exhibited preferential inhibition in cell lines bearing the G12C mutation and potently suppressed pERK in Calu-1 cells at concentration <10μM. RMC-4550 both inhibited cell proliferation and suppressed RAS-GTP and pERK levels in NCI-H358 (lung, KRASG12C/+) and MIA PaCa-2 (pancreas, KRASG12C/G12C) cell lines. RMC-4550 led to caspase 3/7 activation at concentration of 1 and 10μM, indicative of a pro-apoptotic effect in NCI-H358 cells. Oral administration of RMC-4550 dose-dependently inhibited tumor growth in NCI-H358 xenograft mice at dose of 3, 10 and 30mg/kg, qd, and in MIA PaCa-2 xenograft mice at 10, 30 and 60mg/kg, qd, in MIA PaCa-2 xenograft mice, both of which are models of KRASG12C-driven cancer, with downregulated p-ERK observed[1].
作用机制 RMC-4550 is an allosteric inhibitor of SHP2 enzyme. It downregulated RAS-GTP by disrupting the SHP2/SOS1/GRB2 module that is required for GTP-loading of RAS.[1][2]
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.29mL

0.46mL

0.23mL

11.43mL

2.29mL

1.14mL

22.86mL

4.57mL

2.29mL
参考文献

[1]Robert J. N, Franziska H, et al. Efficacy of SHP2 phosphatase inhibition in cancers with nucleotide-cycling oncogenic RAS, RAS-GTP dependent oncogenic BRAF and NF1 loss. bioRxiv. September 14, 2017.

[2]Nichols RJ, Haderk F, et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat Cell Biol. 2018 Sep;20(9):1064-1073.