(R)-STU104   Click here for help

GtoPdb Ligand ID: 12006

Synonyms: (R)-4e [PMID: 35442672]
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: (R)-STU104 is a first-in-class molecule that inhibits the interaction between the proteins kinases TAK1 (mitogen-activated protein kinase kinase kinase 7; MAP3K7) and MKK3 (mitogen-activated protein kinase kinase 3; MAP2K3) [1]. These kinases are part of the inflammatory signalling cascade that culminates in TNF-α production. (R)-STU104 binds to MKK3 at a location that disrupts its interaction with the upstream kinase TAK1. This action perturbs MKK3 phosphorylation by TAK1 and inhibits downstream signal propagation. Blocking TAK1-mediated phosphorylation of MKK3 with (R)-STU104 reduces TNF-α in vitro and in mouse models of chronic ulcerative colitis (UC). In the mouse models (R)-STU104 was a more effective UC treatment than the approved UC drug mesalazine (a PPARγ inhibitor). In addition to TNF-α, (R)-STU104 reduced production of several pro-inflammatory cytokines in vivo, including IL-1β, IL-6, and IL-23.
Click here for help
2D Structure
Click here for help
Click here for structure editor
Physico-chemical Properties
Click here for help
Hydrogen bond acceptors 1
Hydrogen bond donors 0
Rotatable bonds 4
Topological polar surface area 44.76
Molecular weight 298.12
XLogP 2.81
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Click here for help
Canonical SMILES COc1ccc(cc1)[C@H]1CC(=O)c2c1c(OC)cc(c2)OC
Isomeric SMILES O=C1C[C@H](c2ccc(OC)cc2)c2c(OC)cc(OC)cc12
InChI InChI=1S/C18H18O4/c1-20-12-6-4-11(5-7-12)14-10-16(19)15-8-13(21-2)9-17(22-3)18(14)15/h4-9,14H,10H2,1-3H3/t14-/m1/s1
InChI Key OYJBHGSSAJNKJF-CQSZACIVSA-N
Immunopharmacology Comments
(R)-STU104 binds to MKK3 and disrupts its interaction with the upstream kinase TAK1. This action decreases phosphorylation of MKK3, causes selective inhibition of p38 MAPK activation and downstream Mnk1-MK2-elF4E signalling cascades, and culminates in reduced TNF-α production. (R)-STU104 has demonstrated efficacy in mouse models of ulcerative colitis.