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	Vol	Issue	Date	Pages	Journal Short Title
Journal of medicinal chemistry	61	4	2018 Feb 22	1499-1518	J Med Chem

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	Drugs	Efficacy Evidence	Clinical Trials
FN-1501	FN-1501	1	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
FN-1501		FN1501\|FN 1501	CDK2 Inhibitor 31 CDK4 Inhibitor 17 CDK6 Inhibitor 6 FLT3 Inhibitor 69	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).

Gene	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
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