MLK

Necrosulfonamide ((E)-Necrosulfonamide) is a necroptosis inhibitor that targets MLKL and is selective. Necrosulfonamide prevents the MLKL-RIP1-RIP3 necrosomal complex from interacting with its downstream effectors.

Aurantiamide has anti-cancer, anti-inflammatory and antinociceptive activities, it may suppress the growth of malignant gliomas by blocking autophagic flux.Aurantiamide has an anti-neuroinflammatory effect on LPS stimulation through its inhibition of the

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).

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

Ligustroflavone (Nuezhenoside) has anti-inflammatory activity.

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.

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

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.

Cerdulatinib hydrochloride (PRT2070 hydrochloride) is an oral active, multi-targeted tyrosine kinase inhibitor with IC50 of 12 nM/6 nM/8 nM/0.5 nM and 32 nM for JAK1/JAK2/JAK3/TYK2 and Syk, respectively. Also inhibits 19 other tested kinases with IC50 less than 200 nM.

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

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

(E/Z)-Necrosulfonamide is a novel inhibitor of MLKL.

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.

PRT062607 hydrochloride (P505-15 Hydrochloride) is a selective inhibitor of Syk (IC50: 1 nM). It displays at least 80-fold selectivity for Syk over other kinases.

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.

M443 is a potent small molecule inhibitor of MRK that inhibits radiation-induced activation of p38 and Chk2 and can be used in cancer research.

KWCN-41, a selective and efficient RIPK1 kinase inhibitor, exhibits an IC50 value of 88 nM. It specifically targets cell necrosis without affecting apoptosis and possesses anti-inflammatory properties [1].

NecroIr1, an iridium(III) complex, acts as a necroptosis inducer in Cisplatin-resistant lung cancer cells (A549R). It selectively targets mitochondria, causing oxidative stress and reducing mitochondrial membrane potential (MMP). By activating receptor-interacting serine-threonine kinase 3 (RIPK3) and Mixed Lineage Kinase (MLKL), and modulating CDK4 expression, NecroIr1 facilitates cell death mechanisms [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.

Sphingosine-1-phosphate (S1P), a bioactive lipid crucial in numerous signaling pathways, undergoes irreversible degradation by membrane-bound S1P lyase, producing (E)-2-Hexadecenal, a derivative of sphingolipid breakdown. This compound can be oxidized to (2E)-hexadecenoic acid by long-chain fatty aldehyde dehydrogenase before being activated through linkage to coenzyme A. Notably, (E)-2-Hexadecenal induces cytoskeletal reorganization, leading to cell rounding, detachment, activation of JNK pathway targets, and ultimate apoptosis in a variety of cell types. Furthermore, it readily forms aldehyde-derived DNA adducts through reactions with deoxyguanosine and DNA.

MBA-m1 is an MLKL inhibitor that suppresses necroptosis in Mlkl−/−NIH-3T3 cells. Additionally, MBA-m1 alleviates disease conditions in mouse models of dermatitis and abdominal aortic aneurysm induced by MLKL.

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

SZM-1209 is a potent and specific RIPK1 inhibitor with oral activity, displaying a dissociation constant (Kd) of 85 nM. It demonstrates substantial anti-necroptotic efficacy with an EC50 of 22.4 ± 8.1 nM and possesses therapeutic effects against systemic inflammatory response syndrome (SIRS) and acute lung injury (ALI) [1].

NecroIr2, an iridium(III) complex, functions as a necroptosis inducer in cisplatin-resistant lung cancer cells (A549R). It preferentially accumulates in mitochondria, causing oxidative stress and a reduction in mitochondrial membrane potential (MMP). Moreover, NecroIr2 initiates the activation of receptor-interacting serine/threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL), while also regulating CDK4 expression [1].