RIPK3 inhibitor 42   Click here for help

GtoPdb Ligand ID: 10401

Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Compound 42 is reported as a selective inhibitor of receptor-interacting protein kinase 3 (RIPK3), that exhibits potent antinecroptotic activity in vitro, and significant anti-inflammatory action in vivo [1]. Structurally it is a derivative of TAK-632.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 3
Rotatable bonds 9
Topological polar surface area 120.59
Molecular weight 540.03
XLogP 4.29
No. Lipinski's rules broken 0
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Canonical SMILES O=C(Nc1cc(ccc1F)Oc1ccc2c(c1)sc(n2)NC(=O)C1CC1)Nc1cccc(c1)Br
Isomeric SMILES O=C(Nc1cc(ccc1F)Oc1ccc2c(c1)sc(n2)NC(=O)C1CC1)Nc1cccc(c1)Br
InChI InChI=1S/C24H18BrFN4O3S/c25-14-2-1-3-15(10-14)27-23(32)28-20-11-16(6-8-18(20)26)33-17-7-9-19-21(12-17)34-24(29-19)30-22(31)13-4-5-13/h1-3,6-13H,4-5H2,(H2,27,28,32)(H,29,30,31)
Bioactivity Comments
Compound 42 exhibits improved selectivity for RIPK3 over RIPK1 compared to its predecessor TAK-632 [1]. In an in vitro kinase selectivity screen (KINOMEscan® assay) compound 42 targeted six kinases in addition to RIPK3: BRAF (and BRAFV600E), VEGFR2, SRC, PDGFRA and PDGFRB. However, none of these off-targets are involved in the necroptotic signalling pathway, and therefore cannot be responsible for 42s antinecroptotic activity.
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
receptor interacting serine/threonine kinase 3 Primary target of this compound Hs Inhibitor Inhibition 7.1 pKd - 1
pKd 7.1 (Kd 8.1x10-8 M) [1]
receptor interacting serine/threonine kinase 1 Hs Inhibitor Inhibition <5.3 pKd - 1
pKd <5.3 (Kd >5x10-6 M) [1]