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 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]
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