MLKL compound 1   Click here for help

GtoPdb Ligand ID: 9513

Synonyms: compound 23 [PMID: 15990302] | GW806742X
PDB Ligand
Compound class: Synthetic organic
Comment: This small molecule acts as an inhibitor of the activity of mixed lineage kinase domain like pseudokinase MLKL. The compound binds the nucleotide binding site within the MLKL pseudokinase domain and reduces MLKL translocation to the cell membrane, which has the effect of preventing MLKL-driven necroptosis (necroptosis being a form of regulated inflammatory cell death [2]) [1]. This effect is driven by blocking the conformational change in the N-terminal four-helix bundle (4HB) domain of the protein caused by nucleotide binding that is required for membrane translocation and killing activity. This compound was originally identified as a nanomolar potency inhibitor of VEGFR2 tyrosine kinase [3], but note that inhibition of VEGFR2 by another VEGFR2 inhibitor (sorafenib) does not prevent necroptosis, suggesting a direct role for MLKL in this form of cell death, and also demonstrates that targeting the nucleotide binding site of pseudokinases is a novel strategy for modulating signal transduction. In summary, MLKL compound 1 provides a useful tool for investigating necroptosis.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 10
Hydrogen bond donors 4
Rotatable bonds 11
Topological polar surface area 159.95
Molecular weight 573.14
XLogP 4.26
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES O=C(Nc1ccc(cc1)OC(F)(F)F)Nc1ccc(cc1)N(c1ccnc(n1)Nc1cccc(c1)S(=O)(=O)N)C
Isomeric SMILES O=C(Nc1ccc(cc1)OC(F)(F)F)Nc1ccc(cc1)N(c1ccnc(n1)Nc1cccc(c1)S(=O)(=O)N)C
InChI InChI=1S/C25H22F3N7O4S/c1-35(22-13-14-30-23(34-22)31-18-3-2-4-21(15-18)40(29,37)38)19-9-5-16(6-10-19)32-24(36)33-17-7-11-20(12-8-17)39-25(26,27)28/h2-15H,1H3,(H2,29,37,38)(H,30,31,34)(H2,32,33,36)
InChI Key SNRUTMWCDZHKKM-UHFFFAOYSA-N
Classification Click here for help
Compound class Synthetic organic
Synonyms Click here for help
compound 23 [PMID: 15990302] | GW806742X
Database Links Click here for help
BindingDB Ligand 5832
ChEMBL Ligand CHEMBL188381
GtoPdb PubChem SID 336446900
PubChem CID 5329829
RCSB PDB Ligand 6UX
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SynPHARM 84261 (in complex with mixed lineage kinase domain like pseudokinase)
84262 (in complex with mixed lineage kinase domain like pseudokinase)