MLK

MLK-IN-1 (US20140256733A1, compound 68) is a highly potent and selective inhibitor of mixed lineage kinase 3 (MLK-3). It exhibits excellent brain penetration and specifically targets MLK-3.

MLKL-IN-6 (compound P28) is a mixed lineage kinase inhibitor that specifically targets the Mixed Lineage Kinase domain-like (MLKL) protein. It effectively prevents MLKL phosphorylation and oligomerization, which are critical steps in cell necrosis. Additionally, MLKL-IN-6 restrains the death of immune cells, diminishes the expression of adhesion factors, and exhibits low cytotoxicity. Furthermore, it impedes the activation of hepatic stellate cells, decreases levels of liver fibrosis markers, and exerts anti-fibrotic effects [1].

MLKL-IN-2 is an MLKL inhibitor with potential tumorigenic activity for the study of cellular necrosis-related diseases.

PROTAC MLKL Degrader-1 (Compound 36) is a selective PROTAC degrader targeting MLKL, achieving a degradation maximum (D max) over 90%. The compound encompasses modified cereblon (CRBN) ligands and a lenalidomide-linker as part of its structure. It effectively inhibits cell death in a TSZ-induced model of necroptosis.

MLKL-IN-1 is a covalent inhibitor of MLKL with a Kd value of 50 μM.

MLKL-IN-5 is a potent MLKL inhibitor that mediates necroptosis .

URMC-099 is an orally bioavailable, brain penetrant MLK inhibitor (IC50: 19/42/14/150 nM, for MLK1/MLK2/MLK3/DLK), and also inhibits LRRK2 activity (IC50: 11 nM).