Discovery of Novel MLKL PROTAC Degrader for the Treatment of Hepatocellular Carcinoma via Promoting Parthanatos
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Jing Ai
PROVIDER: PXD069462 | iProX | Tue Oct 14 00:00:00 GMT+01:00 2025
REPOSITORIES: iProX
Publications
Discovery of Novel MLKL PROTAC Degraders for the Treatment of Hepatocellular Carcinoma via Promoting Parthanatos.
Chen Chao C Liu Kaiyuan K Wang Xinlei X Yan Ruyu R Dai Yang Y Li Yiming Y Xia Chaoyue C Zhang Yue Y Yang Biyu B Chen Xiangli X Zheng Wei W Geng Meiyu M Yang Yaxi Y Jiang Xifei X Ai Jing J Zhou Bing B
Journal of medicinal chemistry 20260316 6
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, primarily due to its low immunogenicity and immunosuppressive tumor microenvironment. Inducing immunogenic cell death (ICD), a regulated form of cell death with the capacity to enhance tumor immunogenicity and activate antitumor immune responses, has emerged as a pivotal anticancer strategy. Mixed lineage kinase domain-like pseudokinase (MLKL) is a terminal-known obligate effector in the process of necr ...[more]
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2019-09-20 | GSE125625 | GEO
Project description:Mixed lineage kinase domain-like (MLKL) is the executioner in the caspase 8-independent form of programmed cell death called necroptosis. Once Receptor Interacting serine/threonine Protein Kinase 3 (RIPK3) is activated by upstream cell death signals, it phosphorylates MLKL and triggers the oligomerization and membrane translocation required for MLKL induced membrane disruption. Besides phosphorylation, MLKL also undergoes ubiquitylation during the early stages of necroptosis, yet neither the mechanism nor the significance of this event has been demonstrated. Here we show that necroptosis-specific, multi-mono-ubiquitylation of MLKL occurs on biological membranes, and requires its activation and oligomerisation. Inactive MLKL mutants recruited to membranes during necroptosis are ubiquitylated but this results in their proteasome and lysosome dependent turnover. We identified several ubiquitylated lysines however mutation of these did not affect MLKL ubiquitylation in response to a necroptotic stimulus.
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Project description: Not available
| S-EPMC12107161 | biostudies-literature