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

A series of 1-H-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 50 (FN-1501)， which possesses potent inhibitory activities against FLT3， CDK2， CDK4， and CDK6 with IC values in the nanomolar range， shows antiproliferative activities against MV4-11 cells (IC: 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 50 (LD: 186 mg/kg) is safer than AT7519 (32 mg/kg). In MV4-11 xenografts in a nude-mouse model， compound 50 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.