Discovery of 4‑((7<i>H</i>‑Pyrrolo[2,3‑<i>d</i>]pyrimidin-4-yl)amino)‑<i>N</i>‑(4-((4-methylpiperazin-1-yl)methyl)phenyl)‑1<i>H</i>‑pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia

A series of 1-<i>H</i>-pyrazole-3-carboxamide derivatives have been designed and synthesized that exhibit excellent FLT3 and CDK inhibition and antiproliferative activities. A structure–activity-relationship study illustrates that the incorporation of a pyrimidine-fused heterocycle at position 4 of the pyrazole is critical for FLT3 and CDK inhibition. Compound <b>50</b> (FN-1501), which possesses potent inhibitory activities against FLT3, CDK2, CDK4, and CDK6 with IC₅₀ values in the nanomolar range, shows antiproliferative activities against MV4-11 cells (IC₅₀: 0.008 μM), which correlates with the suppression of retinoblastoma phosphorylation, FLT3, ERK, AKT, and STAT5 and the onset of apoptosis. Acute-toxicity studies in mice show that compound <b>50</b> (LD₅₀: 186 mg/kg) is safer than AT7519 (32 mg/kg). In MV4-11 xenografts in a nude-mouse model, compound <b>50</b> can induce tumor regression at the dose of 15 mg/kg, which is more efficient than cytarabine (50 mg/kg). Taken together, these results demonstrate the potential of this unique compound for further development into a drug applied in acute-myeloid-leukemia (AML) therapeutics