Heterocyclic Amides as Kinase Inhibitors.

Abstract

Regulated cell death is essential for the maintenance and development of the immune system and also to facilitate an effective response to exogenous and endogenous stimuli. Programmed necrosis is a major cell-death pathway, which is dependent on receptor interacting protein (RIP1 and RIP3) kinases. RIP1 is a TKL family of serine-threonine kinase that can be triggered by tumor necrosis factor (TNF) family of death receptors, genotoxic stress, pathogen sensors, and so forth. Consequently, necrosis may lead to cell leakage and elimination of cells that cannot die by apoptosis. RIP1 kinase is a RIP homolytic interaction motif (RHIM) domain containing protein with an N-terminal kinase domain and a C-terminal death domain, which interact with other death domain containing proteins such as Fas and TNFR-1, TRAIL-R1 and TRIAL-R2, and TRADD. Unlike RIP1, RIP3 does not contain a death domain; however, both interact via the C-terminal RHIM domain. The deletion of either RIP1 or RIP3 abolishes the TNF- or Fas-induced necroptosis. Binding of RIP3 requires one of the RIP1, DAI, or TRIF partners via a common RIP homotypic interaction motif. A significant role of RIP1 is mediating downstream signals of the death receptor TNRF1. After a ligand binds, the cytosolic portion of TNF receptor 1 (TNFR1) recruits multiple proteins (such as TRAF2/5, TRADD, cIAPs, RIPI) that undergo oligomerization and collectively constitute the signal complex called complex I. Complex I, which is kinase independent provides a platform for the recruitment of downstream kinases and effector proteins to activate the transcription factor NF-κB and mitogen-activated protein (MAP) kinases pathway. NF-κB initiate a survival pathway by mediating the expression of some genes encoding cytoprotective molecules. The TNF can induce NF-κB activation in RIP1-deficient MEFs and other types of cells, which may indicate that RIP1 play a role in complex I-mediated activation of NF-κB. Binding of TNF to its receptor under conditions that promote the deubiquitination of RIPI results in internalization and the formation of complex II or cytosolic death-inducing signaling complex (DISC). Complex II contains deubiquitinated RIP1, caspase-8, and the adaptors TRADD and FADD. RIP1 is involved in the activation of caspase-8 and the onset of programmed apoptotic cell death, which is RIP1 kinase independent. When apoptosis is inhibited in DADD/caspase 8 delection, viral infection, or caspase inhibition, the formation of DISC and the expression of RIP1 leads to RIP1 kinase-dependent possibility, which allows RIP3 to enter the complex and cause phosphorylation by RIP1. This initiate a caspase-independent programmed necrotic cell death through the activation of PGAM5 and MLKL. Programmed necrosis result in the release of danger associated molecular patters (DAMPs) from the cell, which provides “danger signal” to surrounding tissues and cells, inflammasome activation, cytokine production, cellular recruitment, and so forth. Necrosis releases a number of intracellular materials, including SAP130, histones, heat-shock proteins, DNA, high-mobility group protein B1, and RNA, which can trigger inflammatory reactions. However, not all examples of necrosis are proinflammatory because sometimes necrosis inhibit inflammatory reactions. For example, macrophages can engulf necroptotic L929 cells without producing inflammatory cytokines, which indicate an unexpected complexity in the immune response to necrotic cells. Nevertheless, the dysregulation of RIP1 kinase-mediated programmed cell death has been linked to various inflammatory diseases. This was demonstrated by RIP3 knockout mouse, where RIP1-mediated programmed necrosis was completely blocked. In addition, Necrostain-1 an inhibitor of RIP1 activity also blocked RIP1-mediated necrosis. The RIP3 knockout mouse was protective from inflammatory bowel disease, Crohn’s disease, psoriasis, cerulein-induced acute pancreatitis, and sepsis/systemic inflammatory response syndrome (SIRS). Furthermore, Necrostatin-1 is effective in alleviating ischemic brain injury, retinal ischemia/reperfusion injury, Huntington’s disease, cisplatin induced kidney injury, and so forth. Consequently, selective and potent small molecule inhibitor of RIP1 kinase activity could block RIP1-dependent cellular necrosis, suppress macrophage polarization in cancer and thus provide therapeutic benefit in events associated with cell death, DAMPs, inflammation, and combination treatment with immune-modulators. The compounds in this Patent Highlight are RIP1 kinase inhibitors for use in the treatment of RIP1 kinase mediated disease or disorder.