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. 2023 Jun 17;12(12):1653. doi: 10.3390/cells12121653

Figure 1.

Figure 1

Xevinapant mode of action through blocking cIAP1/2 and XIAP: (A) In the intrinsic apoptotic pathway, cytochrome c is released from the mitochondria into the cytosol in response to apoptotic stimuli that cause intracellular stress or DNA damage. Cytochrome c molecules associate with Apaf-1 (apoptotic protease activating factor 1) to form the apoptosome. This leads to activation of caspase 9, followed by activation of caspases 3 and 7, resulting in apoptosis. XIAP inhibits apoptosis by blocking caspases 9, 3 and 7. Xevinapant inhibits XIAP, allowing the release of caspase activity and promotion of apoptotic signaling. (B) In the extrinsic pathway, death receptor ligands such as TNF-α stimulate apoptosis by binding to their membrane receptors. This leads to the assembly of TRADD (TNF receptor type 1-associated death domain protein), TRAF2/5 (TNF receptor associated factor) and protein kinase RIP1. In the presence of cIAP1/2, RIP1 is ubiquitylated, and activation of the apoptotic cascade is inhibited. When cIAP1/2 is blocked by Xevinapant, RIP1 is deubiquitylated and forms a complex with FADD (Fas-associated protein with death domain) and procaspase 8. This leads to activation of caspase 8, followed by caspases 3 and 7, and apoptosis takes place. Alternatively, in the absence of caspase 8, deubiquitylated RIP1 can form a complex with RIP3, called the necrosome. This promotes necrotic signaling and results in necroptosis, a programmed necrotic cell death. (C) cIAP1/2 blocks the noncanonical NF-κB pathway and enables canonical NF-κB signaling. Xevinapant inhibits cIAP1/2 downstream of the TNF-receptor, leading to activation of NIK and noncanonical NF-κB signaling. Proinflammatory cytokines such as TNF-α are released and the antitumor immune response of the tumor microenvironment is stimulated. In addition, Xevinapant inhibits the transcription of prosurvival genes by blocking the canonical NF-κB pathway (modified after [30,31,32,33,34,35,36,37,38,39,40,41,43,44,45,60,61,62] and created with BioRender.com, accessed on 28 April 2023).