MLK

MLK-IN-1 is a potent and selective mixed-lineage kinase 3 (MLK-3) inhibitor, showing excellent brain penetration and high specificity for MLK-3. MLK-IN-1 at 100 nM supports sustained axonogenesis in cultures challenged with HIV-1 Tat-activated microglia and protects neuronal cells from Tat-induced damage, establishing it as a valuable probe for neuroinflammation and neurodegeneration research.

MLK-IN-2 (Compound 9a), with its 3H-imidazole [4,5-b] pyridine structure, serves as a potent Mixed Lineage Kinase 3 (MLK3) inhibitor with an IC50 value of 6 nM. This compound is valuable for research in cancer and neurodegenerative diseases [1].

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

MLKL-IN-1, a covalent inhibitor of MLKL, has a dissociation constant (Kd) of 50 μM.

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 immune cell death, diminishes adhesion factor expression, exhibits low cytotoxicity, impedes hepatic stellate cell activation, decreases liver fibrosis marker levels, and exerts anti-fibrotic effects [1].

PROTAC MLKL Degrader-2, a PROTAC that targets MLKL (Mixed Lineage Kinase), incorporates the PROTAC target protein ligand, E3 ligase ligand Thalidomide, and PROTAC Linker N-Methylpiperazine. The conjugate of the E3 ubiquitin ligase ligand and Linker is Thalidomide-N-Methylpiperazine. This compound exhibits antinecroptotic activity in human cell lines and effectively degrades MLKL in the HT-29 xenograft mouse model.

MLK3-IN-1 (Compound 37) is a selective inhibitor of mixed-lineage kinase 3 (MLK3) with an IC50 of less than 1 nM. It also inhibits FAK with an IC50 of 15.5 μM. In both murine and human liver microsomes, MLK3-IN-1 demonstrates excellent metabolic stability.

MLKL-IN-7 (compound 9) is an MLKL inhibitor that exhibits anti-necrotic activity in HT-29 cells, with an IC50 value of 148.4 nM.

ZBP1/RIP3/MLKL activator 1 (compound 3a) is a synthesized quinoline derivative that can induce DNA damage, elevate intracellular reactive oxygen species (ROS) levels, and trigger apoptosis through the caspase pathway. Furthermore, when apoptosis is inhibited, it facilitates necroptosis via the ZBP1-RIP3-MLKL pathway. This compound is useful in cancer research, particularly for targeting cells with impaired apoptotic mechanisms.

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

PROTAC MLKL Degrader-1 (Compound 36) is a selective PROTAC degrader targeting MLKL, with a degradation maximum (D max) exceeding 90%. The compound incorporates modified cereblon (CRBN) ligands and a lenalidomide-linker within its structure, effectively inhibiting cell death in a TSZ-induced model of necroptosis.

DSPE-PEG2000-CSTSMLKAC is a PEG compound composed of DSPE and CSTSMLKAC. CSTSMLKAC can mediate phage selective homing to ischemic heart tissue. DSPE-PEG2000-CSTSMLKAC is suitable for drug delivery.

DSPE-PEG5000-CSTSMLKAC is a PEG compound consisting of DSPE and CSTSMLKAC. CSTSMLKAC facilitates targeted homing of phages to ischemic heart tissue. This compound can be utilized for drug delivery.

DSPE-PEG1000-CSTSMLKAC is a PEG compound composed of DSPE and CSTSMLKAC. The CSTSMLKAC component facilitates phage-mediated targeting to ischemic cardiac tissue. DSPE-PEG1000-CSTSMLKAC is applicable in drug delivery.

DSPE-PEG3400-CSTSMLKAC is a PEG compound composed of DSPE and CSTSMLKAC. CSTSMLKAC is capable of mediating phage selective homing to ischemic cardiac tissue. DSPE-PEG3400-CSTSMLKAC can be utilized for drug delivery.

CSTSMLKAC is a cyclic sequence comprising nine amino acids, resembling an endogenous peptide sequence. It targets myocardial cells in ischemic heart tissue.

LY-364947 (HTS466284) is a potent ATP-competitive inhibitor of TGFβR-I.

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).

GW806742X is an inhibitor of Mixed Lineage Kinase Domain-Like protein (MLKL) which binds the MLKL pseudokinase domain (Kd: 9.3 μM) with anti-necroptosis activity. GW806742X has activity against VEGFR2.

AZ7550, an active metabolite of AZD9291, inhibits the activity of IGF1R (IC50: 1.6 μM).

TC13172 is a potent and covalent inhibitor that specifically targets the mixed lineage kinase domain-like protein (MLKL), exhibiting significant selectivity for MLKL over the closely related receptor-interacting serine/threonine kinase 1 (RIPK1) and RIPK3 at a concentration of 10 µM.TC13172 effectively inhibits necroptosis induced by the TSZ combination (TNF-α, a Smac mimetic, and Z-VAD-FMK) in HT-29 cells with a EC50 of 2 nM and, at 100 nM, blocks TSZ-induced oligomerization and plasma membrane translocation of MLKL.

NecroX-2 is a cell-permeable necrosis inhibitor with antioxidant properties. NecroX-2 selectively suppresses necrotic cell death triggered by oxidative stress. NecroX-2 does not confer protection against apoptosis induced by staurosporine or etoposide but shows protective effects under conditions such as cold shock, hypoxia, and oxidative stress in vitro.

IM-54 is a cell-permeable, effective, and selective necrosis inhibitor.

P505-15 Acetate is a selective inhibitor of spleen tyrosine kinase that acts by suppressing leukocyte immune function and inflammation and leading to a reduction in arthritis score and attenuated histological damage.