KEAP1 x Nrf2 x CUL3

Last update 23 Jan 2025

Basic Info

Related Targets

KEAP1Nrf2CUL3

Drugs associated with KEAP1 x Nrf2 x CUL3

VVD-065

Target

CUL3 x KEAP1 x Nrf2

Mechanism

CUL3 modulators [+2]

Active Org.

Vividion Therapeutics, Inc.

Originator Org.

Vividion Therapeutics, Inc.

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with KEAP1 x Nrf2 x CUL3

100 Translational Medicine associated with KEAP1 x Nrf2 x CUL3

0 Patents (Medical) associated with KEAP1 x Nrf2 x CUL3

208

Literatures (Medical) associated with KEAP1 x Nrf2 x CUL3

01 Dec 2025·Molecular Biology Reports

Luteolin induces oxidative stress and apoptosis via dysregulating the cytoprotective Nrf2-Keap1-Cul3 redox signaling in metastatic castration-resistant prostate cancer cells

Article

Author: Eryilmaz, Isil Ezgi ; Egeli, Unal ; Cecener, Gulsah ; Colakoglu Bergel, Ceyda ; Arioz, Bilge ; Huriyet, Nuseybe

BACKGROUNDThe treatment of metastatic castration-resistant prostate cancer (mCRPC) is still challenging clinically. Due to the refractor and highly metastatic phenotype of mCRPC, novel therapy strategies need to be investigated. Luteolin, a promising anticancer agent with various biological targets in many cancer types, also has a pro-oxidant effect that selectively triggers ROS and apoptosis. In recent years, among its ROS-mediated mechanisms, the inhibitory effect of luteolin on the nuclear factor-E2-related factor 2 (Nrf2), the main ROS scavenger protein in cancer cells, has been reported. However, no evidence exists that luteolin potentially regulates the Nrf2 or its regulator signaling pathway, Nrf2-Keap1-Cul3 axis, concerning its pro-oxidant effects associated with ROS-triggered apoptosis in any PCa cells or tumor model.METHODS AND RESULTSIn the present study, we investigated for the first time whether the anticancer effect of luteolin is associated with pro-oxidant activity via the regulation of the Nrf2-Keap1-Cul3 redox signaling in PC3 and DU145 mCRPC cells. The results showed that luteolin significantly caused more cytotoxic, apoptotic, and pro-oxidant effects in a dose-dependent manner in mCRPC cells than in WPMY-1 normal prostate fibroblast cells for 72 h. Moreover, significant inhibition of Nrf2-Keap1-Cul3 redox signaling has occurred in response to increasing doses of luteolin in mCRPC cells.CONCLUSIONSThe current study put forth the potential pro-oxidant inhibitory effect of luteolin on the Nrf2-Keap1-Cul3 axis in mCRPC cells for the first time. Thus, luteolin might be an attractive therapy strategy with an inhibitory effect on the cytoprotective Nrf2-Keap1-Cul3 redox signaling for treating mCRPC.

01 Mar 2025·Bioorganic & Medicinal Chemistry Letters

Cyclic vinyl sulfones activate NRF2 to protect from oxidative stress-induced programmed necrosis

Article

Author: Bulatov, Emil ; Gurzhiy, Vladislav ; Davidovich, Pavel ; Khadiullina, Raniya ; Nikolaev, Dmitriy

The NRF2 transcriptional factor is a member of cellular stress response machinery and is activated in response to oxidative stress caused either by cellular homeostasis imbalance or by environmental challenges. NRF2 levels are stringently controlled by rapid and continuous proteasomal degradation. KEAP1 is a specific NRF2 binding protein that acts as a bridge between NRF2 and the E3 ligase Cullin-3. In this study, we examine model cyclic vinyl sulfone derivatives as potential NRF2 activating probes. Previously, we and other authors have found anti-inflammatory properties of these compounds in in vivo models; however, the mechanism of action remained unknown. Here, we show that the naphthohydroquinone derivative LCB1353 efficiently stabilizes NRF2 protein levels and upregulates its target genes. At low 5-10 µM concentrations LCB1353 protects non-small cell lung cancer H1299 cells from ferroptotic death induced by cytotoxic concentrations of RSL3, reducing cell death from 90 % to 5 %. Thus, we suggest that cyclic vinyl sulfones are promising scaffolds for the design of protective molecules for conditions associated with toxic and inflammatory levels of oxidative stress.

01 Dec 2024·Genes, Brain and Behavior

Shared Genetic Links Between Sleep, Neurodevelopmental and Neuropsychiatric Conditions: A Genome‐Wide and Pathway‐Based Polygenic Score Analysis

Article

Author: Fahey, Laura ; Lopez, Lorna M.

ABSTRACTGenetic correlations have been reported between chronotype and both autism (AUT) and schizophrenia (SCZ), as well as between insomnia and attention‐deficit/hyperactivity disorder (ADHD), bipolar disorder (BP), schizophrenia (SCZ) and major depression (MDD). Our study aimed to investigate these shared genetic variations using genome‐wide and pathway‐based polygenic score analyses. We computed polygenic scores using summary statistics from genome‐wide association studies (GWAS) of ADHD (N = 225,534), AUT (N = 46,350), BP (N = 353,899), MDD (N = 500,199) and SCZ (N = 160,779). We tested their performance in predicting chronotype (N = 409,630) and insomnia (N = 239,918) status of UK Biobank participants. For pathway‐based polygenic scores, we restricted genetic variation to SNPs that mapped to genes within 1377 Reactome pathways. Genome‐wide polygenic scores for AUT, BP, MDD and SCZ were associated with an evening chronotype (p < 2.2 × 10−16, p = 4.8 × 10−3, p = 8.07 × 10−4 and p < 2.2 × 10−16, respectively). Polygenic scores for ADHD, AUT, BP, MDD SCZ were associated with insomnia (p < 2.2 × 10−16, p = 2.93 × 10−3, p = 2.9 × 10−7, p < 2.2 × 10−16 and p = 8.86 × 10−3, respectively). While pathway‐based polygenic score analysis identified the KEAP1‐NRF2 (p = 1.29 × 10−8) and mRNA Splicing‐Minor Pathways (p = 1.52 × 10−8) as enriched for genetic variation overlapping between chronotype and BP, the majority of tested pathways yielded null findings, suggesting that specific shared genetic mechanisms between sleep‐related phenotypes and neurodevelopmental/psychiatric conditions (NDPC) may be limited to a subset of pathways. Colocalisation analysis identified BP‐associated SNPs in CUL3 and SF3B1 as being linked to changes in their expression. Our results strengthen evidence for shared genetic variation between NDPC and sleep‐related phenotypes. We identify the KEAP1‐NRF2 and mRNA Splicing‐Minor Pathways as potentially mediating the disrupted circadian rhythm phenotype of BP.

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