Reference Detail

Ref Type Journal Article
PMID (29357250)
Authors Wang Y, Zhi Y, Jin Q, Lu S, Lin G, Yuan H, Yang T, Wang Z, Yao C, Ling J, Guo H, Li T, Jin J, Li B, Zhang L, Chen Y, Lu T
Title 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.
Journal Journal of medicinal chemistry
Vol 61
Issue 4
Date 2018 Feb 22
URL
Abstract Text 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 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 50 (LD50: 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
FN-1501 FN-1501 inhibits FLT3, CDK2, CDK4, and CDK6, resulting in decreased downstream signaling and potentially leading to reduced tumor cell proliferation and tumor growth (PMID: 29357250).
Drug Name Trade Name Synonyms Drug Classes Drug Description
FN-1501 CDK2 Inhibitor 16 CDK4 Inhibitor 12 CDK6 Inhibitor 3 FLT3 Inhibitor 48 FN-1501 inhibits FLT3, CDK2, CDK4, and CDK6, resulting in decreased downstream signaling and potentially leading to reduced tumor cell proliferation and tumor growth (PMID: 29357250).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colon cancer not applicable FN-1501 Preclinical - Cell culture Actionable In a preclinical study, FN-1501 induced cell-cycle arrest decreased proliferation in a colon cancer cell line in culture (PMID: 29357250). 29357250
FLT3 exon 14 ins leukemia sensitive FN-1501 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with FN-1501 reduced phoshorylation of FLT3 and downstream STAT5, ERK, and AKT, induced apoptosis and cell-cycle arrest, and decreased proliferation in a human leukemia cell line harboring a FLT3-ITD mutation in culture, and induced tumor regression in xenograft models (PMID: 29357250). 29357250