necroptosis

Necroptosis-IN-1 is a potent necroptosis inhibitor of RIPK1. It is an analog of Necrostatin-1.

Necroptosis-IN-3 (Cyclohexanecarboxamide, N-(2-thienylmethyl)-) (Compound 69) is a Necroptosis inhibitor that inhibits TNF-α induced necroptosis. Necroptosis-IN-3 (Compound STX1638) also inhibits 11β-HSD1.

(E)-Necrosulfonamide ((E)-Necrosulfonamide) is an inhibitor of necroptosis. Blocks mixed lineage kinase domain-like protein (MLKL), a critical substrate of receptor-interacting serine-threonine kinase 3 (RIP3) during necrosis. Prevents MLKL-RIP1-RIP3 necrosome complex from interacting with downstream necrosis effectors. Binds and inhibits gasdermin D. Inhibits pyroptosis.

Necrostatin 2 racemate (Necrostatin-2 racemate) is an potent and specific inhibitor of RIPK1.

Necrostatin-34 (2-{[3-cyano-4-(4-methylphenyl)-6-oxo-1,4) is a RIPK1 kinase inhibitor, stabilizing RIPK1 kinase in an inactive conformation by occupying a distinct binding pocket in the kinase domain.

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.

Anticancer Agent 146 (Compound 1.19) acts as a necroptosis inducer and demonstrates anti-tumor efficacy in the MDA-MB-231 mouse xenograft model [1].

ZMF-23, a PAK1/HDAC6 dual inhibitor, suppresses PAK1 and HDAC6-mediated aerobic glycolysis and cellular migration while inducing TNF-α-regulated necroptosis and augmenting apoptosis. The compound effectively hampers the Warburg effect and cell motility, positioning it as a potential research tool for triple-negative breast cancer (TNBC) [1].

Necrostatin-1 (Nec-1) (inactive control), an inactive analog of Necrostatin-1, functions as a potent inhibitor of necroptosis [1].

Apostatin-1 (Apt-1) is a novel TRADD inhibitor that binds to a pocket on the N-terminal TRAF2 binding domain of TRADD.

Kuguaglycoside C induces caspase-independent cell death, and is involved, at least in part, in the mechanism underlying cell necroptosis.

673-A is an aldehyde dehydrogenase (ALDH1A) inhibitor that depletes CD133+ cancer stem cells (CSC) in ovarian cancer cell lines. 673-A triggers necroptosis in ovarian CSCs and induces expression of mitochondrial uncoupling proteins (UCP). 673-A also overcomes chemotherapy resistance in vivo.

CDDO-3P-Im is an orally active inhibitor of necroptosis with chemopreventive effects. CDDO-3P-Im can be used in studies about ischemia reperfusion.

ZZW-115 is a potent NUPR1 inhibitor with a Kd of 2.1 μM and is a derivative of Trifluoperazine (TFP). It shows dose-dependent tumor regression without neurological side effects and induces cell death mainly by necroptosis and apoptosis[1] [2].

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].

Cathepsin B, a cysteine protease, plays a role in various forms of programmed cell death, such as apoptosis, pyroptosis, ferroptosis, necroptosis, and autophagic cell death [1].

RIPK1-IN-12 is a potent inhibitor of RIPK1, exhibiting an inhibitory effect on necroptosis in human and mouse cells with EC50 values of 1.6 and 2.9 nM, respectively.

Chlorido[N,N'-disalicylidene-1,2-phenylenediamine]iron(III) is an inducer of ferroptosis.1 It induces ferroptosis, but not apoptosis or necroptosis, in NB1 cancer cells when used at a concentration of 3 μM.1 Chlorido[N,N'-disalicylidene-1,2-phenylenediamine]iron(III) inhibits proliferation of BJAB, NALM-6, Jurkat, MelHO, and MCF-7 cancer cells (IC50s = 0.07, 2.5, 1.5, 3, and 5 μM, respectively), as well as NALM-6 cells resistant to daunorubicin and vincristine when used at concentrations ranging from 0.04 to 0.125 μM.2 |1. Sagasser, J., Ma, B., Baecker, D., et al. A new approach in cancer treatment: Discovery of chlorido[N,N'-disalicylidene-1,2-phenylenediamine]iron(III) complexes as ferroptosis inducers. J. Med. Chem. 62(17), 8053-8061 (2019).|2. Lee, S.-Y., Hille, A., Kitanovic, I., et al. [FeIII(salophene)Cl], a potent iron salophene complex overcomes multiple drug resistance in lymphoma and leukemia cells. Leuk. Res. 35(3), 387-393 (2011).

Necrostatin 2 is an effective necroptosis inhibitor. Necrostatin 2 is also a RIPK1 inhibitor. EC50 for inhibition of necroptosis in FADD-deficient Jurkat T cells treated with TNF-α is 0.05 μM.

Kongensin A is an effective heat shock protein 90 (HSP90) inhibitor that has potential anti-necroptosis and anti-inflammation applications.

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.

RIPK3-IN-4 (Compound 42) is a RIPK3 inhibitor that mitigates necroptosis, inflammatory responses, and HK-2 cell damage. It alleviates acute kidney injury by attenuating Cisplatin- and I R-induced kidney damage, along with associated inflammatory responses and necroptosis [1].

RIPK1 3-IN-1 (Compound 10) is a selective inhibitor of RIPK1 and RIPK3, effectively preventing necroptosis by blocking the phosphorylation of RIPK1, RIPK3, and MLKL [1].

AV123 (compound 12) is a non-cytotoxic RIPK1 inhibitor with an IC50 of 12.12 μM. It blocks TNF-α-induced necroptosis with an EC50 of 1.7 μM, but not apoptotic cell death. AV123 can be used in the study of necrotic chronic conditions such as ischemia-reperfusion injury of the brain, heart, and kidney, inflammatory diseases, neurodegenerative diseases, and infectious diseases [1].

RIPK3-IN-3 (compound 20) is a selective RIPK3 inhibitor with a potent IC50 value of 10 nM, effectively blocking RIPK3-mediated phosphorylation of MLKL, preventing oligomerization and necroptosis induction. Moreover, RIPK3-IN-3 suppresses CXCL5 secretion and impedes AsPC-1 cell migration and invasion [1].

Necrostatin-5 (Nec-5) is a selective RIP1 kinase inhibitor and cell necrosis inhibitor that prevents the death of Fadd-deficient Jurkat cells treated with TNF-α, with an EC50 of 240 nM.

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

ZZW-115 hydrochloride inhibits the activity of NUPR1.

RIPK1-IN-16 is an orally active, potent RIPK1 inhibitor that mitigates excessive inflammation via inhibition of RIPK1-mediated necroptosis in vivo, protecting mice from TNF-induced systemic inflammatory response syndrome and sepsis [1].

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].

Anticancer agent 15, an anticancer agent, exerts its efficacy by elevating intracellular levels of reactive oxygen species (ROS) and inducing cell death in melanoma cancer cells through necroptosis.