Pan-RAS-IN-6 (compound 24) serves as a DUSP6 inhibitor, effectively reducing MAPK activation in the NCI-H1373-Luc model (DUSP6). It concurrently exhibits notable tumor growth inhibition and regression in the NSCLC brain metastasis mouse model. The compound displays high selectivity and potent inhibitory effects, particularly on KRAS mutation-associated signaling pathways. It demonstrates varied inhibitory activities against distinct KRAS mutants and their interacting proteins. The IC 50 values for KRAS G12C, G12D, and G12V are 1.3 nM, 4.7 nM, and 0.3 nM, respectively.

KRas (G12D):4.7 nM, KRas (G12C):1.3 nM, KRas (G12V):0.3 nM

Pan-RAS-IN-6 inhibits cell proliferation in NCI-H23, NCI-H358, NCI-H2444, RKN, and SW620 with IC50 values of 0.17 nM, 0.12 nM, 0.17 nM, 0.045 nM, and 0.1 nM, respectively. The compound demonstrates IC50 values against KRAS G12V, wild-type KRAS, wild-type HRAS, and wild-type NRAS-BRAF with CYPA interaction of 7 nM, 32 nM, 38 nM, and 35 nM, respectively; and in conditions of G12C, G12D, and G12V, the IC50 values for KRAS-BRAF with CYPA interaction are 9.7 nM, 49.5 nM, and 7.1 nM. Additionally, Pan-RAS-IN-6 inhibits pERK with IC50 values of less than 0.6 nM for G12C and G12V, and 0.9 nM for G12D.

Pan-RAS-IN-6, administered orally at a dose of 30 mg/kg once daily, inhibits tumor growth and promotes tumor regression in a mouse model of non-small cell lung cancer (NSCLC) brain tumors. Additionally, this compound reduces the expression of DUSP6 in the brains of the NCI-H1373-Luc model.