RIPK1 Inhibitor

SZM679 is a potent, orally active and selective RIPK1 inhibitor with K_d values of 8.6 nM and >5000 nM for RIPK1 and RIPK3, respectively. SZM679 reverses the tumor necrosis factor-induced systemic inflammatory response. SZM679 decreases the Tau hyperphosphorylation, neuroinflammation, and the RIPK1 phosphorylation level in the hippocampus and cortex. SZM679 can be used in research of Alzheimer's disease (AD).

Necrostatin-34 (Nec-34), a RIPK1 kinase inhibitor, stabilizes RIPK1 kinase in an inactive conformation by occupying a distinct binding pocket in the kinase domain.

RIP1-IN-1 is an orally active RIP1 inhibitor with strong RIP1 binding affinity (K_d: 110 nM). RIP1-IN-1 exhibits strong anti-necroptosis activity. RIP1-IN-1 effectively inhibits the formation of necrosomes by blocking the phosphorylation of RIP1, RIP3 and MLKL signaling pathways. RIP1-IN-1 inhibits necroptosis and can be used in the study of acute liver injury.

RIPK1-IN-25 (WL8) is a blood-brain permeable RIPK1 inhibitor with EC₅₀ and K_d values are 19.9 and 25 nM, respectively. RIPK1-IN-25 can be used in the study of neurometabolic diseases.

Zharp1-163 is a dual inhibitor of ferroptosis and necroptosis. Zharp1-163 effectively blocks ferroptosis by reducing reactive oxygen species (ROS) levels and inhibits necroptosis by potently and selectively targeting RIPK1 kinase activity (K_D = 240 nM; IC₅₀ = 406.1 nM). Zharp1-163 inhibits the cellular activation of RIPK1, RIPK3 and MLKL in response to necroptotic stimulation. Zharp1-163 markedly attenuates TNF-α (HY-P1875)-induced systemic inflammatory syndrome, including the prevention of TNF-α-induced mortality and hypothermia in mice. Zharp1-163 significantly alleviates acute kidney injury associated with both necroptosis and ferroptosis in models induced by Cisplatin (HY-17394) and ischemia-reperfusion. Zharp1-163 can be used for the study of diseases associated with cell death pathways, such as kidney disease.

RIPK1-IN-34 is a selective, brain-penetrant RIPK1 inhibitor (IC₅₀ = 126.70 nM) with almost no inhibitory effect on RIPK3 (IC₅₀ ＞ 10, 000 nM). RIPK1-IN-34 offers substantial neuroprotection by inhibiting the phosphorylation of RIPK1, RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL) within the necroptosis pathway. RIPK1-IN-34 shows the neuroprotective effect in a rat middle cerebral artery occlusion (MCAO) model. RIPK1-IN-34 can be used for the study of anti-acute ischemic stroke (AIS).

RIPK1-IN-37 is an RIPK1 inhibitor and a ligand for the target protein for PROTAC LD5097 (HY-179234). RIPK1-IN-37 can be used to synthesize PROTAC.

Tat-ASIC1a (1-20) (mouse, rat) is a competitive ASIC1a membrane-penetrating peptide. Tat-ASIC1a (1-20) (mouse, rat) has significantly neuroprotection effects, and reduces neuronal damage against acidotoxicity by targeting the ASIC1a-RIPK1 pathway and auto-inhibitory mechanism. Tat-ASIC1a (1-20) (mouse, rat) effectively protects brains from ischemic injury in ischemic stroke mice model. Tat-ASIC1a (1-20) (mouse, rat) can be used for neurodegenerative diseases research, such as Huntington disease and Parkinson’s disease.

RIPK1-IN-18 (compound i) is a potent inhibitor of RIPK1. RIPK1-IN-18 can be used in autoimmune diseases research.

VWK147 is a second-generation HSP90 C-terminal domain (CTD) inhibitor. VWK147 targets the CTD dimerization interface, prevents HSP90 CTD dimerization, disrupts co-chaperone PPID binding to HSP90 CTD, and inhibits HSP90 chaperone function dependent on dimerization. VWK147 reduces protein levels of HSP90 client proteins ULK1, RIPK1, and CDK4 without inducing a heat shock response. VWK147 induces cell death, including apoptosis, in Cisplatin (HY-17394)-sensitive and -resistant urothelial carcinoma cells. VWK147 induces LC3-II accumulation, inhibits autophagosome-lysosome fusion to block canonical autophagy, and induces non-canonical LC3 lipidation independent of ULK1 and PIK3C3 complexes. VWK147 can be used for the research of urothelial carcinoma.

RIPK1-IN-38 is an orally active RIPK1 inhibitor with an IC₅₀ value of 27 nM. RIPK1-IN-38 can inhibit the phosphorylation of RIPK1 and its downstream signaling molecules RIPK3 and MLKL. RIPK1-IN-38 exhibits anti-necroptotic activity. RIPK1-IN-38 has excellent anti-inflammatory efficacy in both the SIRS model and GVHD model. RIPK1-IN-38 can be used for the research of inflammatory and immune-related diseases.

RIPK1-IN-11 is a potent and orally active RIPK1 inhibitor (K_d=9.2 nM; IC₅₀=67 nM). RIPK1-IN-11 inhibits necroptosis in both human and mouse cells (EC₅₀=17-30 nM). Anti-inflammatory activity.

PB830 (compound 41) is a potent receptor interacting protein 1 kinase (RIP1) Inhibitor with an IC₅₀ of <100 nM for human RIP1. PB830 has an EC₅₀ of 1-100 nM in the cell necrosis assay.

LT-1339-553 is a selective, orally active RIPK1 inhibitor with IC₅₀ values of 4.32, 95.74 and 84.33 nM against RIPK1, RIPK2 and RIPK3, respectively. LT-1339-553 exerts anti-necroptotic activity by inhibiting the AKT/PI3K/NF-κB pathway and the IL-17 pathway. LT-1339-553 reduces liver injury, inflammatory responses and collagen deposition. LT-1339-553 can be used in studies related to schistosomiasis-induced liver fibrosis.

RIPK1-ligand-2 is a RIPK1 inhibitor. RIPK1-ligand-2 can be used for synthesis of PROTAC RIPK1 Degrader-1 (HY-175370).

RIPK1-IN-14 (Compound 41) is a potent inhibitor of RIPK1 with an IC₅₀ value of 92 nM. RIPK1-IN-14 shows a significant anti-necroptotic effect in a necroptosis model in U937 cells.

SZM-1209 is an orally active, potent and specific RIPK1 inhibitor, with a K_d of 85 nM. SZM-1209 exhibits high anti-necroptotic activity (EC₅₀=22.4 ± 8.1 nM). SZM-1209 shows anti-SIRS (systemic inflammatory response syndrome), and anti-ALI (acute lung injury) effects.

RIPK1-IN-13 (compound 28) is a selective inhibitor for receptor-interacting serine/threonine-protein kinase 1 (RIPK1), the inhibitory activity is measured by ADP-Glo Kinase Assay with a pK_i of 7.66. RIPK1-IN-13 inhibits human leukaemia cells U937 with a pIC₅₀ of 7.2.

RIPK1-IN-36 (Example 4.1) is a RIPK1 inhibitor with an EC₅₀ of <25 nM. RIPK1-IN-36 can be used for the study of RIPK1-related diseases.

(Neurodegenerative diseases) NDs-IN-1 (Compound 3g) inhibits the activities of key enzymes such as hBACE-1, hAChE and hMAO-B. NDs-IN-1 is a novel non-covalent multi-target inhibitor. NDs-IN-1 is mainly used in the study of neurodegenerative diseases.