RIP kinase
Cytokine stimulation, pathogen infection, DNA damage or inflammation can initiate cellular signaling pathways that lead to diverse responses, including immune cell activation and death. The receptor-interacting protein (RIP) kinase family members have emerged as essential sensors of intracellular and extracellular stresses. They have been demonstrated to play an important role in not only inflammation and other immune responses, but also in death-inducing processes. The RIP kinases now contain seven members, all of which share a homologous kinase domain but have different functional domains.
RIP1 contains a C-terminal death domain, through which RIP1 can be recruited to signaling complexes that initiate different pathways. RIP2 bears a caspase activation and recruitment domain (CARD). RIP3 has a C-terminus that is unique among all known protein domains. However, a RIP homotypic interaction motif (RHIM) found in the intermediate domain of RIP1 was also identified in the C-terminus of RIP3. The RHIM domain is likely to mediate protein–protein interactions, since it is required for the interaction between RIP3 and RIP1. RIP4 and RIP5 are characterized by the ankyrin repeats in their C-terminus. RIP6 and RIP7 have a leucine-rich repeat motif that may have a role in the recognition of damage-, pathogen- or stress-associated molecular patterns. Additionally, they both harbor Ros of complex proteins/C-terminal of Roc domains. Upon binding of GTP to the Roc domain, the RIP6 protein kinase activity is stimulated. Evidence was provided that the C-terminal of Roc domain might play a role in transmitting stimulating signals to the kinase domain. It is reasonable to deduce that the C-terminal domains of RIP family members play key roles in determining the diverse functions of different RIP kinases.
RIP1 is a key mediator of several signaling pathways that lead to the activation of MAPKs and NF-κB, as well as cell death. RIP2 is critical for signaling from NOD-like receptors and can trigger MAPKs and NF-κB activation. The role of RIP3 is major in the induction of necrosis: it may participate in the process of apoptosis and regulate NF-κB signaling. RIP4 mainly functions in the activation of JNK and NF-κB pathways. These RIP kinases are involved in many cellular signaling pathways, regulating inflammatory responses and cell death or survival. Current knowledge of RIP kinases has suggested therapeutic potential in targeting RIP family kinases in the treatment of diseases of inflammation, ischemia and neurodegeneration.
References
1.Zhang D,et al. Cell Mol Immunol. 2010;7(4):243–249.
RIP1 contains a C-terminal death domain, through which RIP1 can be recruited to signaling complexes that initiate different pathways. RIP2 bears a caspase activation and recruitment domain (CARD). RIP3 has a C-terminus that is unique among all known protein domains. However, a RIP homotypic interaction motif (RHIM) found in the intermediate domain of RIP1 was also identified in the C-terminus of RIP3. The RHIM domain is likely to mediate protein–protein interactions, since it is required for the interaction between RIP3 and RIP1. RIP4 and RIP5 are characterized by the ankyrin repeats in their C-terminus. RIP6 and RIP7 have a leucine-rich repeat motif that may have a role in the recognition of damage-, pathogen- or stress-associated molecular patterns. Additionally, they both harbor Ros of complex proteins/C-terminal of Roc domains. Upon binding of GTP to the Roc domain, the RIP6 protein kinase activity is stimulated. Evidence was provided that the C-terminal of Roc domain might play a role in transmitting stimulating signals to the kinase domain. It is reasonable to deduce that the C-terminal domains of RIP family members play key roles in determining the diverse functions of different RIP kinases.
RIP1 is a key mediator of several signaling pathways that lead to the activation of MAPKs and NF-κB, as well as cell death. RIP2 is critical for signaling from NOD-like receptors and can trigger MAPKs and NF-κB activation. The role of RIP3 is major in the induction of necrosis: it may participate in the process of apoptosis and regulate NF-κB signaling. RIP4 mainly functions in the activation of JNK and NF-κB pathways. These RIP kinases are involved in many cellular signaling pathways, regulating inflammatory responses and cell death or survival. Current knowledge of RIP kinases has suggested therapeutic potential in targeting RIP family kinases in the treatment of diseases of inflammation, ischemia and neurodegeneration.
References
1.Zhang D,et al. Cell Mol Immunol. 2010;7(4):243–249.
Apoptosis
RIP kinase
-
RIPK2-IN-5
产品货号 : M37339
cas no: 2885227-09-6
RIPK2-IN-5 (compound 14) 是一种高亲和力、优异选择性的RIPK2抑制剂,IC50值为5.1nM。 RIPK2-IN-5具有细胞抗炎作用,并能以剂量依赖性方式减少MDP诱导的TNF-α的分泌。 RIPK2-IN-5 在人肝微粒体中表现出中等稳定性。 RIPK2-IN-5可用于免疫疾病的研究。 -
Zharp2-1
产品货号 : M37243
cas no: 2772600-18-5
Zharp2-1 是一种口服有效的 RIPK2 抑制剂,与炎症性肠病 (IBD) 高度相关。Zharp2-1 阻断胞壁酰二肽 (muramyl dipeptide,MDP) 诱导或单核细胞增生李斯特菌感染诱导的炎症细胞因子转录和释放。Zharp2-1 可有效减轻 MDP 诱导的小鼠腹膜炎,或改善 DNBS 诱导的大鼠结肠炎。 -
Oditrasertib
产品货号 : M36303
cas no: 2252271-93-3
Oditrasertib 是一种受体相互作用蛋白激酶 1 (RIPKl) 抑制剂,其 IC50 值低于 100 nM。Oditrasertib 可用于研究涉及炎症或细胞死亡的疾病。 -
RIPK1-IN-9
产品货号 : M35690
cas no: 2682889-57-0
RIPK1-IN-9 (实施例 45) 是一种二氢萘啶酮化合物,一种有效的选择性 RIPK1 抑制剂。 RIPK1-IN-9 抑制 U937 细胞 (IC50=2 nM) 和 L929 细胞 (IC50=1.3 nM)。 -
GSK872 HCl(1346546-69-7 free base)
产品货号 : M35224
cas no: 2703752-81-0
GSK-872 hydrochloride 是 RIPK3 抑制剂,高亲和力结合 RIP3 激酶结构域,IC50为1.8 nM,并抑制激酶活性,IC50为1.3 nM。GSK-872 hydrochloride 降低 RIPK3 介导的坏死 (necroptosis) 和随后的 HMGB1 的细胞质易位和表达,并改善早期脑损伤中的脑水肿和神经功能缺损。