MLKL

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

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.

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.

BIX-01294 trihydrochloride is an inhibitor of G9a histone methyltransferase.In a cell-free assay, the IC50=2.7 μM for G9a histone methyltransferase.

BIX-01294 is an G9a Histone Methyltransferase inhibitor(IC50 : 1.9 μM).

MLKL-IN-5 is a potent small molecule inhibitor of MLKL. By specifically targeting MLKL, it prevents its phosphorylation by RIPK3 and subsequent oligomerization, thereby blocking the transmission of the necroptosis signaling pathway. It is an important pharmacological tool molecule for studying the pathological mechanisms of necroptosis in various inflammatory diseases, neurodegenerative diseases, and cancer.

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 ligand-2 is a PROTAC ligand for mixed lineage kinase domain-like pseudokinase (MLKL) with a KD value of 9.408 μM. It forms a network of hydrogen bonds and hydrophobic interactions with specific residues of MLKL, stabilizing it in hepatocytes. MLKL ligand-2 is utilized in the synthesis of PROTAC MLKL Degrader-3.

PROTAC MLKL Degrader-3 (compound C116) is an MLKL PROTAC degrader. It induces the degradation of MLKL via ubiquitination, relying on the proteasome and cereblon pathways. This compound is applicable in hepatocellular carcinoma research.

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-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.

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.

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

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.

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

Antitumor agent-87 is a potent compound exhibiting high antitumoral activity, with a Ki value of 0.23 µM for CYP1A1. It demonstrates antiproliferative effects and induces cell cycle arrest at the G2/M phase, underscoring its effectiveness as an antitumor agent.

Liriodenine is a natural alkaloid that induces apoptosis in various cancer cells by targeting caspase-3 and caspase-9, and exhibits antimicrobial, antifungal, antitumour, antiviral, and antiplatelet aggregation activities.

Thalidomide-N-methylpiperazine functions as an E3 Ligase Ligand-Linker Conjugate and is instrumental in the synthesis of PROTAC MLKL Degrader-2. This compound demonstrates antinecroptotic activity in human cell lines and effectively degrades MLKL in the HT-29 xenograft mouse model.

RIP3 Activator 1 (compound C8) is an effective RIP3 activator that inhibits cell growth and induces necroptotic cell death (necroptosis) and autophagy through the RIP3/p62/Keap1 signaling pathway. Additionally, this compound enhances the expression of p-MLKL and promotes the accumulation of LC3-II and p62 proteins.

TopoisomeraseI/II inhibitor 8 (Compound Ru7) is a dual catalytic inhibitor of TopoisomeraseI/II that induces DNA damage and activates PARP-1, leading to the activation of RIPK1, RIPK3, and MLKL, ultimately causing necroptosis. It shows significant anticancer activity by effectively targeting cancer cell nuclei and inducing cell death through necroptosis, offering substantial clinical potential in overcoming resistance in cancer treatment.

Anticanceragent 267 (Compound 5q) serves as an activator of RIPK3 and MLKL. It effectively inhibits the proliferation of several cancer cell lines, with IC50 values of 9.79, 10.77, and 5.94 μM for MDA-MB-231, MDA-MB-486, and MCF-7, respectively. The compound induces cell cycle arrest at the subG1 phase and triggers necroptosis in MDA-MB-231 cells. Additionally, Anticanceragent 267 demonstrates antitumor activity in mouse xenograft models.

RIP1-IN-1 is an orally bioavailable RIP1 inhibitor with a high binding affinity (Kd: 110 nM). This compound exhibits significant activity against necroptosis and effectively suppresses necrosome formation by inhibiting the phosphorylation of RIP1, RIP3, and MLKL pathways. RIP1-IN-1 can inhibit necroptosis and is applicable in research on acute liver injury.