MI-538 stands out by inhibiting the growth of MLL leukemia cells, achieving a GI50 of 83 nM, and demonstrates specificity by not affecting the growth of HL-60 and HM-2 control cell lines, which lack MLL translocations, up to concentrations of 6 μM. This selectivity underscores its efficacy against cells transformed by MLL fusion proteins. MI-538's strong cellular activity is attributed to its low nanomolar affinity (Kd=6.5 nM) for menin, potentially enhanced by improved binding affinity and cellular uptake. Treatment with MI-538 significantly diminishes Hoxa9 and Meis1 gene expressions in MLL-AF9 cells, with about 100 nM reducing Hoxa9 expression by roughly 50% and even more substantially affecting Meis1 expression[1].
MI-538 动物研究
Animal study
MI-538 treatment markedly decreases MV4;11 tumor volumes by approximately 80% without significant toxicity, as evidenced by a minimal (<10%) reduction in body weight. The pharmacokinetic profile of MI-538 is favorable, exhibiting significant plasma concentration peaks (Cmax), prolonged exposure (AUC), reduced clearance rates, and a half-life of about 1.6 hours, alongside high oral bioavailability (around 50%)[1].
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