Ask about this productRelated genes to: DHODH Blocking Peptide
- Gene:
- DHODH NIH gene
- Name:
- dihydroorotate dehydrogenase (quinone)
- Previous symbol:
- -
- Synonyms:
- -
- Chromosome:
- 16q22.2
- Locus Type:
- gene with protein product
- Date approved:
- 1993-06-29
- Date modifiied:
- 2015-09-11
Related products to: DHODH Blocking Peptide
Related articles to: DHODH Blocking Peptide
- Pyrimidine is required for the biosynthesis of DNA, RNA, glycoproteins, and phospholipids. Dihydroorotate dehydrogenase (DHODH) is a crucial flavin-dependent enzyme in mitochondria involved in the de novo pyrimidine synthesis and has been considered a significant drug target for diseases involving viral infections and parasitic diseases. Moreover, it has gained attention as a promising target for cancer treatment in recent years. This review introduces the structural and biochemical properties of DHODH and elaborates on its role in mitochondrial energy metabolism and ferroptosis. It summarizes the role of DHODH in cancer occurrence and development, as well as the in vivo effects and related regulatory mechanisms of DHODH inhibition. Moreover, it systematically discusses the latest developments in drug development based on the selective inhibition of DHODH, and introduces the therapeutic potential of DHODH inhibitors in cancer, bacterial and viral infections, and immune disorders. - Source: PubMed
Publication date: 2026/04/29
Guan XiaoyingLi JinchunGuan XiaoliHao CuirongZhang YajieYan Hong - This study aimed to create innovative transfersomes (TRFs) consisting of a lipid blend and a chemical permeation enhancer for efficient transdermal delivery of leflunomide (LFN). Leflunomide, a dihydroorotate dehydrogenase inhibitor, is mainly used to manage rheumatoid arthritis (RA). Oral consumption of LFN for RA can lead to adverse systemic effects; hence, local application is advisable. To develop topical dosage form of LFN, transfersomes with improved skin permeation capabilities were fabricated. The vesicle diameter of LFN-TRF was determined to be 181.2 ± 2.17 nm, zeta potential of - 29.2 ± 0.06 mV, PDI of 0.259 ± 0.006, and encapsulation percentage (EE) of 86.5 ± 3.45%. Notably, the developed formulation exhibited slow and sustained release of up to 78.87% of LFN over 24 h. The drug permeation from the nanocarriers was found to be around 67% for the LFN-TRF-gel and 55.33% for the LFN-gel. Skin irritation assessments indicated no signs of irritation, inflammation, or toxicity, affirming the formulation's nontoxic and biocompatible characteristics. In vivo studies demonstrated higher anti-inflammatory and anti-arthritic activity than conventional gel. In summary, this study presents a viable alternative for formulating effective topical LFN preparation using transfersomes. - Source: PubMed
Publication date: 2026/05/01
Moravkar KailasThakare RutujaKumawat VivekSapkal SandipChalikwar ShaileshNirbhavane Pradip - Dihydroorotate dehydrogenase (DHODH), a key enzyme in de novo pyrimidine biosynthesis, has recently emerged as a therapeutic target in various cancers. We have previously identified a pivotal role of DHODH in the initiation of cutaneous squamous cell carcinoma (cSCC), the second most common type of non-melanoma skin cancer. We also showed that pharmacological inhibition of this enzyme suppresses ultraviolet (UV)-induced tumor formation. However, the key mechanisms driving the anticancer activity of DHODH inhibition remain unexplored in cSCC. We investigated the biological consequences of pharmacological and genetic DHODH inhibition in cSCC using xenograft models derived from two human cell lines, A431 and SCC13, implanted in immunodeficient NSG mice. DHODH activity was suppressed pharmacologically with leflunomide (LFN) and the potent DHODH inhibitor PTC299, or genetically via lentiviral shRNA-mediated DHODH silencing (shDHODH). Proteomic and metabolomic analyses were integrated with histopathological, immunohistochemical, and immunoblotting evaluations to delineate the downstream effects of DHODH blockade. Comprehensive proteomic and metabolomic profiling revealed that DHODH inhibition induces a coordinated adaptive program involving keratinization, differentiation, redox homeostasis, and metabolic stress responses. Histological and immunostaining analyses demonstrated marked reductions in Ki67-positive proliferating cells and a corresponding increase in pan-cytokeratin (PanCK) and keratin 10 (Krt10) expression, indicative of enhanced epithelial differentiation. These changes were most pronounced in PTC299-treated and shDHODH xenografts, whereas LFN displayed minimal or no efficacy in SCC13 tumors. DHODH inhibition drives tumor differentiation and suppresses proliferation in cSCC, highlighting metabolic dependency as a potential therapeutic vulnerability. PTC299 exhibited superior antitumor activity and differentiation-inducing capacity compared with LFN. These findings position DHODH as a promising target for bioenergetic vulnerability-based cancer therapy in advanced or treatment-resistant cSCC. - Source: PubMed
Publication date: 2026/04/28
Khalife FerialMuzotte ElodieNaji FatimaMahfouf WalidIzotte JulienPinson BenoîtClaverol StéphaneAmoedo NiveaFayyad-Kazan HusseinDousset LeaRossignol RodrigueRezvani Hamid-Reza - Cancer-associated isocitrate dehydrogenase (IDH) mutations sensitize gliomas to replication stress, although the underlying mechanisms are unclear. IDH-mutant enzymes synthesize ( )-2-hydroxyglutarate (R2HG), which broadly inhibits 2-oxoglutarate-dependent enzymes. We performed forward genetic screens targeting all 2-oxoglutarate-dependent enzymes and discovered that KDM6 histone demethylases play a vital role in protecting cells from replication stress. Genetic or R2HG-mediated repression of KDM6 catalytic activity sensitized glioma cells to disparate replication stress-inducing drugs, including Ataxia-telangiectasia and Rad3-related (ATR) and dihydroorotate dehydrogenase (DHODH) inhibitors. This liability is generalizable because KDM6A loss-of-function mutations commonly observed in urothelial carcinomas sensitized bladder cancer cells to DHODH inhibition, thereby phenocopying IDH mutations in glioma. To exploit these oncogene-induced replication stress vulnerabilities, we developed an effective, on-target, and well-tolerated DHODH inhibitor, GLIO-1, that is poised for clinical translation. Collectively, we reveal KDM6 activity as a fundamental determinant of replication stress sensitivity and nominate pan-cancer, mechanism-based biomarkers of ATR and DHODH inhibitor efficacy. - Source: PubMed
Publication date: 2026/04/17
Tsai Alexander C-YLin Mathew DPuliyappadamba Vinesh TJunginger Dorothy MDonovan Victoria GKaplan Eleanor GDrepanos Laura MWakimoto HiroakiCahill Daniel PLosman Julie AMouw Kent WAbdullah Kalil GDoench John GNash DuaneVitt DanielGege ChristianKohlhof HellaMcBrayer Samuel KKaelin William GShi Diana D - Differentiation therapy offers a promising approach in acute myeloid leukemia (AML) by overcoming the developmental block that maintains leukemic blasts. Increasing evidence indicates that DNA replication stress can promote differentiation rather than cytotoxicity; however, the metabolic mechanisms linking replication stress to differentiation remain poorly defined. Here, we investigated how perturbations in nucleotide metabolism regulate replication stress-driven differentiation. Using metabolomic and functional analyses in AML cell lines, we show that agents inducing differentiation through replication stress, including 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), dihydroorotate dehydrogenase (DHODH) inhibition, and low-dose cytarabine, converge on disruption of nucleotide pool balance. Low-dose AICAr induced a pyrimidine-purine imbalance, S phase arrest, and enhanced differentiation, whereas high-dose reduced these effects. Although brequinar and cytarabine altered nucleotide metabolism through distinct mechanisms, differentiation induced by all agents was abolished by supplementation with high levels of ribo- and deoxyribonucleosides, confirming that nucleotide imbalance is a central driver. We further identify ribonucleotide reductase (RNR) as a critical modulator of this process. Replication stress induced context-dependent regulation of RNR subunits, with RRM2 upregulated in p53-mutant U937 cells and the p53-responsive RRM2B isoform predominating in p53-wild-type MOLM-13 cells. Consistent with these differences, RRM2 depletion enhanced differentiation in U937 cells without affecting viability but impaired differentiation and survival in MOLM-13 cells. These findings position nucleotide metabolism as a key regulator of AML differentiation and suggest that combining RNR-targeted and checkpoint-modulating strategies could optimize therapeutic responses. - Source: PubMed
Publication date: 2026/04/24
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