Targeting RIPK1 for the treatment of human diseases

Abstract

RIPK1 kinase has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases. This was supported by extensive studies which demonstrated that RIPK1 is a key mediator of apoptotic and necrotic cell death as well as inflammatory pathways. Furthermore, human genetic evidence has linked the dysregulation of RIPK1 to the pathogenesis of ALS as well as other inflammatory and neurodegenerative diseases. Importantly, unique allosteric small-molecule inhibitors of RIPK1 that offer high selectivity have been developed. These molecules can penetrate the blood-brain barrier, thus offering the possibility to target neuroinflammation and cell death which drive various neurologic conditions including Alzheimer's disease, ALS, and multiple sclerosis as well as acute neurological diseases such as stroke and traumatic brain injuries. We discuss the current understanding of RIPK1 regulatory mechanisms and emerging evidence for the pathological roles of RIPK1 in human diseases, especially in the context of the central nervous systems.

Keywords: RIPK1; apoptosis; inflammation; necroptosis; neurodegeneration.

Fig. 1.

Schematic presentation of the RIPK1-dependent signaling events in response to TNF-α. Signaling bifurcates into poly-ubiquitin-dependent NF-κB activation mediated by receptor-bound Complex I through TAK1 and IKK kinase complexes. Alternatively, RIPK1 kinase activation and deubiquitination/reubiquitinatiuon promotes formation of secondary cytosolic Complex IIa and IIb. Depending on the activity of caspase-8 and RIPK3, signaling by Complexes II may lead to apoptosis, necroptosis, and increased inflammatory gene expression. The activating events are shown by arrows; however, it is not meant to indicate direct connections between signaling nodes. In many cases, mechanistic details remain to be uncovered.

Fig. 2.

Mode of inhibition of RIPK1 by necrostatins and other type III inhibitors. (A) Rendering of the crystal structure of Nec-1s with RIPK1 (85). Nec-1s is occupying the back pocket localized behind the ATP binding center. This pocket is created due to the outward movement of αC-helix, resulting in the loss of ionic pair between catalytic Lys45 and Glu63 of αC-helix. The other side of the pocket is formed by the DLG motif (shown in green) in the inactive DLG-in conformation (catalytic Asp146 facing away from the active center) and the activation segment, which immediately follows the DLG motif (shown in red). Ser161 residue of the activation segment, which forms a critical hydrogen bond with the indole of Nec-1s, is also shown. (B) A number of additional type III inhibitors have been recently developed by GlaxoSmithKline and Takeda, including clinical candidate GSK′772 (–91). These molecules (rendered in red, based on published crystal structures) occupy the same back pocket as Nec-1s (shown in green) in the same Glu-out/DLG-out conformation but extend into the ATP binding pocket, which may contribute to the increased affinity.

Fig. 3.

Bimodal RIPK1 activation in neurological disease leads to progressive deleterious signaling loop to promote neuroinflammation and cell death. Activation of RIPK1 in either microglia oligodendrocytes or neurons can initiate a degenerative signaling loop. This cascade relies on microglial-driven deleterious inflammation and necrotic cell death in the CNS. Microglial. RIPK1 regulates a degenerative neuroinflammatory milieu in the CNS that can lead to necroptosis of oligodendrocytes and axonal degeneration. Neurons with damaged mitochondria and lysosomes may undergo necroptosis. In turn, necroptosis of either oligodendrocytes or neurons promotes inflammation by driving the cell-autonomous expression of proinflammatory cytokines in microglia as well as by releasing of the cellular content from necrotic cells (including DAMPs) into the CNS. This deleterious axis creates a progressive inflammatory and degenerative environment in the brain to promote the progression of neurodegenerative disease.