Compound class:
Synthetic organic
Comment: Compound 7d is a FLT3 inhibitor [1]. It was identified as a lead compound in a medicinal chemistry study to find novel chemical scaffolds that offer improved FLT3 inhibition, and that provide compounds with potential clinical oncology therapeutic value for FLT3-driven cancers. Similar levels of inhibition of wild type and D835Y-mutated FLT3 enzymes suggests that compound 7d is a Type I (ATP binding site) kinase inhibitor. In comparison to quizartinib, a single dose of compound 7d produces a longer-lived inhibition of FLT3 and STAT5 phosphorylation in xenograft mice.
Ligand Activity Visualisation ChartsThese are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts. ✖ |
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| Bioactivity Comments |
| Compound 7d inhibits activity of the oncogenic FLT3-internal tandem duplications (ITD) mutant kinase with an IC50 of 3 nM in a biochemical assay [1]. Potent inhibition of the FLT3D835Y point mutation is observed, with an IC50 of 8 nM (similar to the wild type IC50 of 13 nM). It inhibits proliferation of AML cells carrying FLT3-ITD mutations (MV4-11 cells; GI50 2 nM), and FLT3-ITD positive MOLM-13 cells (GI50 1 nM). The inhibition of MV4-11 cell proliferation is replicated in vivo, in xenografts grown in immunocompromised mice. Compound 7d also inhibits proliferation of K562 cells which don't have the FLT3-ITD mutation, although with a much lower efficacy (GI50 380 nM) [1]. In a selectivity screening panel of 309 kinases, 10 nM compound 7d inhibited several other kinases by > 90% (including PDGFRα/β, CLK1, TRK, QIK, CaMK2δ, SIK, YES, FMS, CAMK2γ, KITD816V, MNK2, ACK, and Src). |
| Selectivity at catalytic receptors | ||||||||||||||||||||||||||||||||||
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