necroptosis-in-1

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

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.

Antiangiogenic agent 6 (Pt-1) effectively inhibits angiogenesis and induces necroptosis in tumor cells.

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.

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.

R1-ICR-5 is a selective PROTAC degrader targeting serine/threonine-protein kinase 1 (RIPK1). Mediated by VHL, R1-ICR-5 promotes the degradation of RIPK1, disrupting the TNFR1 and TLR3/4 signaling hubs, enhancing NF-κB, MAPK, and IFN signal output, and facilitating RIPK3 activation and necroptosis induction. R1-ICR-5 holds potential for research in cancer and inflammatory diseases.

RIP1 kinase inhibitor 9 (compound SY-1) is a selective inhibitor of RIP kinase. It effectively reduces central inflammatory responses caused by seizures. RIP1 kinase inhibitor 9 also obstructs Z-VAD-FMK-induced necroptosis in HT-29 cells, with an EC50 of 7.04 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.

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).

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].

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

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].

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].

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].

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].

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-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].

VDX-111, an analog of vitamin D, exhibits cytotoxicity in ovarian cancer cells by upregulating the RIPK1 RIPK3 pathway and inducing necroptosis. It also promotes the expression of cytokines and demonstrates antitumor activity in a mouse model [1].

Necroptosis-IN-5 (Compound 26) is an orally active inhibitor of necroptotic cell death (necroptosis). This compound also exhibits potent inhibitory activity against receptor-interacting protein kinase 1 (RIPK1). It can be utilized in research related to inflammatory diseases, neurodegenerative disorders, and cancer associated with necroptosis.

Necroptosis-IN-4 is an effective inhibitor of necroptosis, specifically targeting RIP kinase 1 (RIPK1) without inhibitory activity against RIPK3. It exhibits weak inhibitory effects on VEGFR1 2 and PDGFR-α.