MODULATION OF MIXED LINEAGE KINASE DOMAIN-LIKE PROTEIN SIGNALING

摘要

The invention is based on a method of modulating the activation or inhibition of Mixed lineage kinase domain-like (MLKL) protein, or a MLKL variant protein, via modulating the the intramolecular interaction between the C-terminal helix (He) of the psK domain and a hydrophobic groove in the MLKL protein. The invention provides methods and compounds for to selectively target the herein firstly disclosed intramolecular interaction of MLKL protein. Based on the herein disclosed essential intramolecular rearrangement of MLKL, the invention provides small molecules capable of specifically inhibiting mouse or human MLKL. The invention provides uses, including medical applications such as treatments, of MLKL driven conditions including necroptosis, cell trafficking, pathological immune responses and/or inflammation.