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
Click here for structure editor
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
SMILES / InChI / InChIKey
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-
InChI Key SAEGVASGMTZGFI-AQYVVDRMSA-N
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
Key to terms and symbols Click column headers to sort
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.