MRX-2843

MRX-2843 (UNC2371) is an orally active, ATP-competitive dual MERTK and FLT3 tyrosine kinases inhibitor (TKI) with enzymatic IC₅₀s of 1.3 nM for MERTK and 0.64 nM for FLT3, respectively^[1]. IC50 & Target: MERTK, FLT3^[1] In Vitro: In the Kasumi-1 cell line, treatment with MRX-2843 results in dose-dependent inhibition of MERTK phosphorylation. Decreased phosphorylation is evident at concentrations as low as 10 nM, with near-complete abrogation of MERTK activation at 100 to 300 nM. Similarly, treatment of Kasumi-1 cells with MRX-2843 mediates inhibition of downstream signaling through pathways important for tumor cell survival and proliferation. MRX-2843 treatment results in a decrease in relative cell numbers, with an IC₅₀ of 143.5±14.1 nM, indicating that MRX-2843 significantly inhibits tumor cell proliferation and/or survival. Similarly, there are 34.1%±5.6% and 67.1%±2.7% apoptotic and dead cells in NOMO-1 cultures treated with 150 nM or 300 nM MRX-2843, respectively, compare with 6.8%±0.7% in vehicle-treated cultures (P<0.001). Treatment with 50 nM and 100 nM MRX-2843 results in 62.3%±6.4% and 84.1%±7.8% inhibition of colony formation, respectively, in Kasumi-1 cultures (P<0.01). Similarly, in NOMO-1 cultures, colony formation is inhibited by 54.8%±18.1% in response to treatment with 100 nM MRX-2843 (P<0.001). In MOLM-14 cells, treatment with MRX-2843 inhibits phosphorylation of FLT3 and downstream signaling through STAT5, ERK1/2, and AKT. Activation of FLT3 and its signaling pathways is almost completely abrogated by treatment with 50 nM MRX-2843, indicating somewhat higher cellular potency against FLT3 relative to MERTK^[1]. In Vivo: MRX-2843 is 78% orally bioavailable at a dose of 3 mg/kg with a C_max of 1.3 μM and a t_1/2 of 4.4 hours. In MOLM-14 parental xenografts, both quizartinib and MRX-2843 increase median survival compare with that of vehicle-treated mice (172.5 days versus 40 days and 121 days versus 36 days, respectively, P<0.001). In this model, quizartinib is more effective than MRX-2843 (P<0.005), although higher doses of MRX-2843 are not evaluated. In MOLM-14:D835Y xenografts, quizartinib prolongs survival compare with that of vehicle-treated mice, but the effect is minimal (median survival 45 days vs. 36 days, P<0.001). In MOLM-14:F691L xenografts, treatment with MRX-2843 prolongs survival by almost 2-fold in NSG and NSGS mice (median survival 87 vs. 44.5 days and 87 vs. 48 days, respectively, P<0.005). Increased survival is observed in response to treatment with MRX-2843 versus quizartinib, but the difference is only significant in NSG mice^[1].