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Last update 08 May 2025

IKKα x IKKβ

Last update 08 May 2025

Basic Info

Related Targets

IKKαIKKβ

Drugs associated with IKKα x IKKβ

JRA-003

Target

IKKα x IKKβ

Mechanism

IKKα inhibitors [+1]

Active Org.-

Originator Org.

University of Michigan

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

INH14

Target

IKKα x IKKβ

Mechanism

IKKα inhibitors [+1]

Active Org.-

Originator Org.

Medical University of Innsbruck

Active Indication-

Inactive Indication

Inflammation

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with IKKα x IKKβ

100 Translational Medicine associated with IKKα x IKKβ

0 Patents (Medical) associated with IKKα x IKKβ

674

Literatures (Medical) associated with IKKα x IKKβ

01 Jun 2025·Veterinary Microbiology

Cepharanthine mitigates NIBV-induced pyroptosis via the MDA5/NF-κB/NLRP3 signaling pathway

Article

Author: Huang, Cheng ; Guo, Xiaoquan ; Ding, Mengbing ; Wu, Meiqin ; Liu, Ping ; Liu, Zhenni ; Tang, Ruoyun ; Gao, Xiaona ; Li, Ying ; Qi, Qiurong

This study elucidates the mechanism through which cepharanthine (CEP) mitigates NIBV-induced pyrodeath in renal tubular epithelial cells by modulating the MDA5/NF-κB/NLRP3 signaling pathway. Primary renal tubular epithelial cells (RTECs) were isolated from one-day-old Hy-Line Brown chicks and subsequently assigned to four groups. The C+CEP and N + CEP groups received 0.5 μM CEP, while the NIBV and N + CEP groups were exposed to 1 MOI of the SX9 strain of NIBV. The study shows that CEP significantly reduces NIBV load (P < 0.05) and decreases the mRNA and protein levels of MDA5/NF-κB/NLRP3 signaling components, such as MDA5, ISP-1, TRAF6, TAK1, NF-κB, IKKα, IKKβ, NLRP3, caspase-1, IL-1β, and IL-18, upon NIBV infection (P < 0.05 or P < 0.01). Moreover, CEP markedly reduced cellular pyroptosis (P < 0.001) and lactate dehydrogenase (LDH) activity (P < 0.01). Flow cytometry and fluorescence-based assays corroborated these findings, revealing a substantial diminution in pyroptosis post-NIBV infection in CEP-treated cells (P < 0.01). Laser confocal microscopy revealed a clear decrease in NLRP3-associated red fluorescence foci after CEP treatment. These results highlight that CEP could mitigate NIBV-induced pyroptosis in RTECs by modulating the MDA5/NF-κB/NLRP3 signaling pathway.

04 May 2025·Autophagy

Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survival

Article

Author: Winklhofer, Konstanze F. ; Mari, Muriel C. ; Balta, Denise ; Scheuer, Christoph ; Behrends, Christian ; Zellner, Suzanne ; Vandrey, Julia ; Zein, Laura ; Zunke, Friederike ; Van Wijk, Sjoerd J. L. ; Bader, Verian ; Dietrich, Marvin ; Weinelt, Nadine

Lysosomes are the major cellular organelles responsible for nutrient recycling and degradation of cellular material. Maintenance of lysosomal integrity is essential for cellular homeostasis and lysosomal membrane permeabilization (LMP) sensitizes toward cell death. Damaged lysosomes are repaired or degraded via lysophagy, during which glycans, exposed on ruptured lysosomal membranes, are recognized by galectins leading to K48- and K63-linked poly-ubiquitination (poly-Ub) of lysosomal proteins followed by recruitment of the macroautophagic/autophagic machinery and degradation. Linear (M1) poly-Ub, catalyzed by the linear ubiquitin chain assembly complex (LUBAC) E3 ligase and removed by OTULIN (OTU deubiquitinase with linear linkage specificity) exerts important functions in immune signaling and cell survival, but the role of M1 poly-Ub in lysosomal homeostasis remains unexplored. Here, we demonstrate that L-leucyl-leucine methyl ester (LLOMe)-damaged lysosomes accumulate M1 poly-Ub in an OTULIN- and K63 Ub-dependent manner. LMP-induced M1 poly-Ub at damaged lysosomes contributes to lysosome degradation, recruits the NFKB (nuclear factor kappa B) modulator IKBKG/NEMO and locally activates the inhibitor of NFKB kinase (IKK) complex to trigger NFKB activation. Inhibition of lysosomal degradation enhances LMP- and OTULIN-regulated cell death, indicating pro-survival functions of M1 poly-Ub during LMP and potentially lysophagy. Finally, we demonstrate that M1 poly-Ub also occurs at damaged lysosomes in primary mouse neurons and induced pluripotent stem cell-derived primary human dopaminergic neurons. Our results reveal novel functions of M1 poly-Ub during lysosomal homeostasis, LMP and degradation of damaged lysosomes, with important implications for NFKB signaling, inflammation and cell death.Abbreviation: ATG: autophagy related; BafA1: bafilomycin A₁; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CRISPR: clustered regularly interspaced short palindromic repeats; CHUK/IKKA: component of inhibitor of nuclear factor kappa B kinase complex; CUL4A-DDB1-WDFY1: cullin 4A-damage specific DNA binding protein 1-WD repeat and FYVE domain containing 1; DGCs: degradative compartments; DIV: days in vitro; DUB: deubiquitinase/deubiquitinating enzyme; ELDR: endo-lysosomal damage response; ESCRT: endosomal sorting complex required for transport; FBXO27: F-box protein 27; GBM: glioblastoma multiforme; IKBKB/IKKB: inhibitor of nuclear factor kappa B kinase subunit beta; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; IKK: inhibitor of NFKB kinase; iPSC: induced pluripotent stem cell; KBTBD7: kelch repeat and BTB domain containing 7; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LCD: lysosomal cell death; LGALS: galectin; LMP: lysosomal membrane permeabilization; LLOMe: L-leucyl-leucine methyl ester; LOP: loperamide; LUBAC: linear ubiquitin chain assembly complex; LRSAM1: leucine rich repeat and sterile alpha motif containing 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NBR1: NBR1 autophagy cargo receptor; NFKB/NF-κB: nuclear factor kappa B; NFKBIA/IĸBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; OPTN: optineurin; ORAS: OTULIN-related autoinflammatory syndrome; OTULIN: OTU deubiquitinase with linear linkage specificity; RING: really interesting new gene; RBR: RING-in-between-RING; PLAA: phospholipase A2 activating protein; RBCK1/HOIL-1: RANBP2-type and C3HC4-type zinc finger containing 1; RNF31/HOIP: ring finger protein 31; SHARPIN: SHANK associated RH domain interactor; SQSTM1/p62: sequestosome 1; SR-SIM: super-resolution-structured illumination microscopy; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TH: tyrosine hydroxylase; TNF/TNFα: tumor necrosis factor; TNFRSF1A/TNFR1-SC: TNF receptor superfamily member 1A signaling complex; TRIM16: tripartite motif containing 16; Ub: ubiquitin; UBE2QL1: ubiquitin conjugating enzyme E2 QL1; UBXN6/UBXD1: UBX domain protein 6; VCP/p97: valosin containing protein; WIPI2: WD repeat domain, phosphoinositide interacting 2; YOD1: YOD1 deubiquitinase.

11 Apr 2025·Central Nervous System Agents in Medicinal Chemistry

Exploring the Potential of Dolutegravir in Alzheimer's Disease Treatment: Insights from Network Pharmacology and In Silico Docking Studies

Article

Author: Rathi, Karishma M. ; Bhole, Ritesh P. ; Karwa, Pawan N. ; Sakle, Nikhil S. ; Undale, Vaishali R. ; Wavhale, Ravindra D.

Background:The search for effective treatments for neurodegenerative diseases, particularly Alzheimer's disease, has been fraught with challenges. Alzheimer's disease accounts for 60-80% of dementia cases globally, affecting approximately about 50 million people. Currently, drug repurposing has emerged as a promising strategy in new drug development, attracting significant attention from regulatory agencies, such as the US FDA.Aim:This study aimed to investigate the potential therapeutic role of dolutegravir in Alzheimer's disease (AD) treatment using a novel network pharmacology approach. Specifically, it explored the interaction of dolutegravir with key molecular targets involved in AD pathology, predicted its effects on relevant biological pathways, and evaluated its viability as a new therapeutic candidate.Objective:This study employed a network pharmacology framework to evaluate dolutegravir, an antiretroviral drug, as a potential treatment for Alzheimer's disease, shedding light on its possible therapeutic mechanisms.Method:A network pharmacology approach was used to predict the drug targets of dolutegravir. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify interacting pathways. Additionally, protein- protein interaction (PPI) network analysis was conducted to assess key interactions and molecular docking studies were performed to evaluate the binding affinity of dolutegravir to the predicted targets.Result:PPI network analysis revealed that dolutegravir interacted with several key targets, including BRAF, mTOR, MAPK1, MAPK3, NOS1, BACE1, CAPN1, CASP3, CASP7, CASP8, CHUK, IKBKB, PIK3CA, and PIK3CD. KEGG pathway analysis suggested that dolutegravir could influence amyloid-beta formation, amyloid precursor protein metabolism, and the cellular response to amyloid-beta. Molecular docking results showed the highest binding affinity of dolutegravir for PI3KCD (-8.5 kcal/mol) and MTOR (-8.7 kcal/mol).Conclusion:The findings indicated that dolutegravir holds significant potential in modulating key pathways involved in Alzheimer's disease pathogenesis. These results provide a strong foundation for further investigations into the therapeutic efficacy and safety of dolutegravir in the treatment of Alzheimer's disease. The use of drug repurposing strategies, leveraging Dolutegravir's established pharmacological profile, offers a promising route for accelerated therapeutic development in AD.

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