compound 7d [PMID: 29672049]   

GtoPdb Ligand ID: 9937

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.
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 8
Hydrogen bond donors 3
Rotatable bonds 7
Topological polar surface area 106.15
Molecular weight 490.32
XLogP 3.5
No. Lipinski's rules broken 0
Canonical SMILES NC1CCC(CC1)Nc1nc(Nc2ccc(cc2)CN2CCOCC2)c2c(n1)n(cn2)C1CCCC1
Isomeric SMILES N[C@@H]1CC[C@H](CC1)Nc1nc(Nc2ccc(cc2)CN2CCOCC2)c2c(n1)n(cn2)C1CCCC1
InChI InChI=1S/C27H38N8O/c28-20-7-11-22(12-8-20)31-27-32-25(24-26(33-27)35(18-29-24)23-3-1-2-4-23)30-21-9-5-19(6-10-21)17-34-13-15-36-16-14-34/h5-6,9-10,18,20,22-23H,1-4,7-8,11-17,28H2,(H2,30,31,32,33)/t20-,22-
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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Target Sp. Type Action Value Parameter Concentration range (M) Reference
fms related receptor tyrosine kinase 3 Hs Inhibitor Inhibition 7.9 pIC50 - 1
pIC50 7.9 (IC50 1.3x10-8 M) [1]
Description: In a biochemical assay.