Discovery and evaluation of 3-phenyl-1H-5-pyrazolylamine-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3).

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Lin WH, Hsieh SY, Yen SC, Chen CT, Yeh TK, Hsu T, Lu CT, Chen CP, Chen CW, Chou LH, Huang YL, Cheng AH, Chang YI, Tseng YJ, Yen KR, Chao YS, Hsu JT, Jiaang WT

Discovery and evaluation of 3-phenyl-1H-5-pyrazolylamine-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3).

Bioorg Med Chem. 2011 Jul 15;19(14):4173-82. doi: 10.1016/j.bmc.2011.06.016. Epub 2011 Jun 13.

PubMed ID

21708468 [ View in PubMed

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Abstract

Preclinical investigations and early clinical trial studies suggest that FLT3 inhibitors offer a viable therapy for acute myeloid leukemia. However, early clinical data for direct FLT3 inhibitors provided only modest results because of the failure to fully inhibit FLT3. We have designed and synthesized a novel class of 3-phenyl-1H-5-pyrazolylamine-derived compounds as FLT3 inhibitors which exhibit potent FLT3 inhibition and high selectivity toward different receptor tyrosine kinases. The structure-activity relationships led to the discovery of two series of FLT3 inhibitors, and some potent compounds within these two series exhibited comparable potency to FLT3 inhibitors sorafenib (3) and ABT-869 (4) in both wt-FLT3 enzyme inhibition and FLT3-ITD inhibition on cell growth (MOLM-13 and MV4;11 cells). In particular, the selected compound 12a exhibited the ability to regress tumors in mouse xenograft models using MOLM-13 and MV4;11 cells.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Sorafenib	Receptor-type tyrosine-protein kinase FLT3	IC 50 (nM)	54	N/A	N/A	Details
Sorafenib	Vascular endothelial growth factor receptor 1	IC 50 (nM)	18	N/A	N/A	Details
Sorafenib	Vascular endothelial growth factor receptor 2	IC 50 (nM)	3	N/A	N/A	Details