brequinar (DUP 785) / BMS, Clear Creek Bio - LARVOL DELTA

Pyrimidine Metabolism Drives Cystic Fibrosis Lung Disease (NACFC 2026) - "DNPPS was inhibited using siRNA targeting DHODH (DNPPS rate-limiting enzyme) and pharmacological inhibitors (leflunomide, teriflunomide, brequinar, and gemcitabine). CFTR correction was achieved using elexacaftor/tezacaftor/ivacaftor (ETI)... We show that airway remodeling and P. aeruginosa infection in the CF lung are tightly linked via altered pyrimidine signaling, a metabolic configuration promoted by CFTR mutations and mitochondrial impairment. We also reveal that this adverse environment is correctable, opening new therapeutic targets to improve CF patients' health."

Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases • CFTR

Therapeutic Co-targeting of Oxidative Phosphorylation and Pyrimidine Synthesis Restores Gemcitabine Response in Pancreatic Ductal Adenocarcinoma. (PubMed, Transl Res) - "Co-targeting OXPHOS (antimycin A) or DHODH (brequinar) with gemcitabine produced Loewe synergy in vitro and suppressed growth of gemcitabine-resistant xenografts without affecting body weight. Collectively, these findings established MRPS22/MRPL3 as translation-level drivers of PDAC metabolic fitness and nominate OXPHOS/DHODH blockade as a rational combination strategy to overcome gemcitabine resistance."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ABCC3

A NanoBiT-based high-throughput assay system for monitoring osteoclast fusion. (PubMed, Anal Biochem) - "In addition, luciferase activity was inhibited by cyclosporin A in a dose-dependent manner and completely abolished by Dcstamp knockout, demonstrating its validity for chemical screening and for evaluating genes involved in osteoclast fusion. Using this platform, we screened approximately 2,300 known bioactive compounds and identified THZ-P1-2, a phosphatidylinositol-5-phosphate 4-kinase type 2 inhibitor, and Brequinar, a dihydroorotate dehydrogenase inhibitor, as novel modulators of osteoclast fusion. Compared with fluorescence-based assays, this luminescence-based system minimizes false-positive signals caused by cellular or compound autofluorescence and provides superior sensitivity and quantifiability. Furthermore, the assay is rapid, simple, and highly compatible with high-throughput screening, making it a useful platform for studying osteoclast fusion and for screening compounds that modulate this process."

Journal • IL4

NLRP3 inflammasome activation is associated with type 1 inflammation and neutrophil activation in pyoderma gangrenosum across human and murine models. (PubMed, JID Innov) - "This study aimed to identify conserved pathogenic mechanisms by integrating analyses of human PG lesions and a brequinar-induced PG-like murine model and to assess therapeutic relevance. In the murine model, both prednisolone and avacopan suppressed inflammatory cytokine expression and neutrophil activation; however, only avacopan significantly improved wound healing. Collectively, these findings suggest that NLRP3 inflammasome activation is associated with type 1 inflammation and neutrophil extracellular trap formation and may represent a PG-associated inflammatory pathway."

Journal • Preclinical • Dermatology • Inflammation • Pain • Pyoderma Gangrenosum • NLRP3

Exploring the Role of the LCN2-DHODH Interaction in Mitochondrial Ferroptosis During Sepsis-Induced Myocardial Injury and LPS-Induced HL-1 Cardiomyocyte Injury. (PubMed, Int J Mol Sci) - "Importantly, pharmacological blockade of DHODH by Brequinar reversed the reduction of p-STAT3 induced by LCN2 silencing...Pharmacological inhibition of DHODH abrogates the cardioprotective effect of LCN2 knockdown by restoring STAT3 phosphorylation. These findings provide novel insights into the prevention and treatment of sepsis-induced myocardial injury."

Journal • Infectious Disease • Septic Shock • DHODH • GPX4 • LCN2

Dihydroorotate Dehydrogenase Inhibitors are Potent Antiviral Agents against Henipaviruses and Arenaviruses. (PubMed, Antiviral Res) - "Among eleven primary hits, five compounds-Farudodstat, Atovaquone, PTC299, hDHODH-IN-7, and Brequinar-were prioritized based on antiviral potency. Notably, PTC299 exhibited a selectivity index exceeding 500. Together, these in vitro findings indicate that DHODH inhibitors have potential as potent broad-spectrum host-directed antivirals, especially against high-consequence and emerging viruses."

Journal

Nucleotide Imbalance and Ribonucleotide Reductase Isoforms Regulate Replication Stress–Induced Differentiation in Acute Myeloid Leukemia (EACR 2026) - "We investigated whether disruption of nucleotide metabolism represents a central driver of replication stress–induced differentiation and examined the role of ribonucleotide reductase (RNR) subunits in modulating this process.Material and AML cell lines (U937, MOLM-13, THP-1) were treated with AICAr, the DHODH inhibitor brequinar, or low-dose cytarabine. These findings identify nucleotide imbalance as a key metabolic regulator of AML differentiation and suggest that RNR isoform composition influences cellular responses to replication stress."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • RRM2 • RRM2B • TP53

SCREENING MITOCHONDRIAL-TARGETING COMPOUNDS IN AML IDENTIFIES MITOTAM AS A BROAD VENETOCLAX-SENSITIZER (EHA 2026) - "Cells were exposed (72h) to MitoTam (TPP-conjugated, mitochondria-targeted tamoxifen derivative), brequinar (DHODH inhibitor) or SK1-In-1 (SPHK1 inhibitor). Annexin V and JC-1 assays support mitochondrial dysfunction and apoptosis as associated features. These findings support mitochondrial targeting with MitoTam as a strategy to overcome venetoclax resistance in AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Inflammatory Arthritis • Leukemia • Metabolic Disorders • ANXA5 • SPHK1

Machine learning-assisted screening of natural product database for the identification of novel chalcone-based derivative as a potent DHODH inhibitor in cancer therapy. (PubMed, Discov Oncol) - "Overall, we hypothesize that NPACT00730 has inhibitory activity against DHODH and represents a computationally prioritized DHODH inhibitor candidate exhibiting predicted multi-cell-line anticancer sensitivity, warranting further experimental validation."

Journal • Oncology

Diselenide-Bridged Iron-Porphyrin MOF for MRI-Guided Radiotherapy via Triple-Pathway Ferroptosis. (PubMed, Int J Nanomedicine) - "This system employs a siderophore-based framework PCN(Fe) as the core, loaded with two specific drugs: RAS-selective lethal compound 3 (RSL3) to block the glutathione peroxidase 4 (GPX4) pathway, and brequinar (BQR) to inhibit the dihydroorotate dehydrogenase (DHODH) pathway...PRBP demonstrates favorable T1-weighted magnetic resonance imaging performance, significantly inhibits tumor cell proliferation in vitro, effectively suppresses 4T1 tumor growth in vivo, and exhibits good biosafety. PRBP induces ferroptosis through multiple targets, providing a potent strategy to overcome radiotherapy resistance."

Journal • Oncology • GPX4

Unmasking the apoptotic potential of DHODH inhibition through targeting adaptive mitophagy. (PubMed, Front Cell Dev Biol) - "However, the efficacy of DHODH inhibitors, such as brequinar (BQR), is often constrained by modest single-agent cytotoxicity, necessitating the exploration of combination therapies...This combination leads to enhanced mtROS accumulation and severe lipid peroxidation, ultimately triggering caspase-dependent apoptosis, while ferroptosis does not appear to be the dominant mechanism under these conditions. Our findings identify mitophagy as a key mechanism of resistance to DHODH inhibition and provide a strong rationale for a combinatorial strategy to enhance the therapeutic efficacy of this class of drugs."

Journal • Oncology

Structural Basis for Potent Inhibition of Human DHODH by Quinoline-4-carboxylic Acid Derivatives. (PubMed, ACS Omega) - "In parallel, ADME modeling predicted a lower Log P for 2d compared with brequinar, pointing to more favorable physicochemical properties. Together, these results establish compound 2d as a potent and drug-like HsDHODH inhibitor and illustrate how integrated computational and structural approaches can elucidate binding determinants of known scaffolds and guide future inhibitor design."

Journal • Immunology • Oncology

Targeting dihydroorotate dehydrogenase (hDHODH) beyond the barrier: discovery of MEDS700 as blood-brain barrier permeable hDHODH inhibitor. (PubMed, Eur J Med Chem) - "An in vivo pharmacokinetic experiment demonstrated that MEDS700 was able to cross the blood-brain barrier, maintaining therapeutically relevant intracerebral concentrations for up to 24 h after oral administration. Our findings establish MEDS700 as a potent, safe, metabolically stable hDHODH inhibitor, indicating it as a promising candidate for the treatment of hard-to-reach brain tumors."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Hematological Disorders • Oncology • Solid Tumor

Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells. (PubMed, Cell Death Discov) - "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. 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."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • RRM2 • RRM2B

Metabolic dependency on de novo pyrimidine synthesis in platinum resistant ovarian cancer (AACR 2025) - "Background: High grade serous ovarian cancer (OC) is lethal due to near universal development of resistance to platinum-based chemotherapy.Materials and We used cisplatin resistant (Cis-R) cells generated by repeated cisplatin treatment of sensitive (Cis-S) OC cell lines, transcriptomic and metabolomic analyses to identify key metabolic pathways associated with platinum resistance...Inhibition of this pathway using the DHODH inhibitor brequinar (BRQ) decreased cell viability and induced expression changes in genes of the mitochondrial electron transport in Cis-R compared with Cis-S cells... Our results support that Cis-R cells acquire dependency on the de novo pyrimidine synthesis and maintain relatively low levels of mitochondrial oxidation, rendering Cis-R cells and tumors vulnerable to inhibitors of this pathway."

Platinum resistant • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

Inhibition of pyrimidine synthesis and the cell cycle in mesothelioma (AACR 2025) - "BAY2402234 is an extremely potent inhibitor of cell growth in multiple mesothelioma cell lines and 59-1,881 times more potent than brequinar; 2) BAY2402234 and dinaciclib act synergistically, suggesting an interaction between pyrimidine biosynthesis and one or more of the following CDKs: CDK1, CDK2, CDK5, and/or CDK9; and 3) BAY2402234 results in increased PD-L1 expression and increased cytokine pathway mRNA expression, suggesting the potential for enhancement of immune checkpoint blockade."

IO biomarker • Mesothelioma • Oncology • Solid Tumor • CCNA1 • CCND1 • CDK1 • CDK2 • CDK9 • CDKN1A • PD-L1

Broad-spectrum antiviral screening reveals pyrimidine biosynthesis as a target for inhibiting measles virus replication. (PubMed, Antiviral Res) - "Furthermore, brequinar exhibited an additive antiviral effect when combined with remdesivir, a direct-acting antiviral drug. Collectively, these findings demonstrated brequinar as a potent inhibitor of MeV replication through targeting the pyrimidine biosynthetic pathway, supporting its potential of repurposing as a therapeutic candidate against MeV."

Journal • Infectious Disease • Measles

Structure-function mapping of DHODH shows deviations in protein structure (AACR 2024) - "We performed saturating mutagenesis screens to identify mutations in DHODH that confer resistance to brequinar and BAY2402234, two highly potent DHODH inhibitors. We found that the structure of DCU-bound DHODH differs from previously published DHODH structures in two important ways: (1) there appears to be a second point of ingress into the active site of DHODH next to the CoQ tunnel that may be able to accommodate a highly non-polar molecule such as CoQ/DCU and (2) the 'flap' covering the DHO/orotate ingress/egress region of DHODH, which is 'closed' in inhibitor-bound DHODH, is 'open' in DCU-bound DHODH. We are currently working to solve the crystal structure of DHODH A58T bound to inhibitor and DCU to ask if DCU can access the active site of DHODH through an alternative hydrophobic tunnel and if DHODH A58T remains in the 'open' configuration when bound to drug."

Oncology

PDE3A promotes ER positive beast cancer progression by preventing ERα ubiquitination degradation (AACR 2025) - "We identified an important role of PDE3A-ERα feedback loop in the ER+BC progress and resistance to endocrine therapy, representing a future biomarker and therapeutic target of ER+BC."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • PDE3A • SPOP

Neuronal Differentiation of GBM-Initiating Cells Combined with Elimination of Undifferentiated Cells Preserves Motor Function. (PubMed, Cells) - "The sequential application of ISX9 and the DHODH inhibitor brequinar (BRQ), which successfully eradicated undifferentiated GICs, not only promoted neuronal differentiation but also inhibited GIC tumorigenesis in the mouse brain, leading to prolonged survival and preservation of motor function in tumor-bearing mice. Furthermore, pathological analysis revealed that this combination not only reduced the size of GIC brain tumors but also facilitated the formation of synapse-like structural contacts between GIC-derived cells and host mouse neurons, suggesting remodeling of the tumor-neural interface within the tumor-developed area. Collectively, these findings suggest that the modulation of tumorigenic GIC differentiation may represent a strategy to preserve neural circuit integrity within the tumor-bearing brain."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Integrating network pharmacology, microbiomics, and metabolomics to uncover the therapeutic effect of Liubao tea on osteoarthritis. (PubMed, Front Immunol) - "Additionally, Brequinar, a de novo pyrimidine synthesis inhibitor, was used to verify the role of pyrimidine metabolism...The molecular docking results demonstrated that Eupatilin, 5,6,7,8-Tetramethoxyflavone, and 5-Hydroxy-6,7,3',4',5'-Pentamethoxyflavone exhibited potential interactions with the hub targets TP53, IL6, and TNF. Liubao tea attenuates OA progression by modulating the composition of the gut microbiota and inhibiting the pyrimidine metabolism pathway, highlighting its potential as a novel natural therapeutic agent for OA."

Journal • Immunology • Oncology • Osteoarthritis • Pain • Rheumatology • Transplantation • IL1B • IL6 • TNFA • TP53

Dual metabolic reprogramming by metal-polyphenol nanoplatform enhances ferroptotic therapy for triple-negative breast cancer. (PubMed, J Colloid Interface Sci) - "This work reveals for the first time that brequinar (BQR, a DHODH inhibitor) exerts dual-edged effects on ferroptotic therapy against 4T1 cells: besides its well-known disruption of cellular redox balance for ferroptosis sensitization, BQR-intervened pyrimidine metabolism blocks tumor growth, accompanied by up-regulation of lipid droplets (LDs), which paradoxically aggravates ferroptosis resistance...This work helps to accelerate DHODH inhibitors' clinical translation by elucidating previously overlooked mechanisms limiting DHODH inhibitors' efficacy and proposing synchronous DGAT1 inhibition as a countermeasure. The fabricated nanoweapon AB@HA-TA/Fe presents a novel dual metabolic intervention paradigm for ferroptosis sensitization, proposing an innovative framework for ferroptosis-integrated combination therapy of TNBC."

Journal • Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Triple Negative Breast Cancer • GPX4

[4 + 2] Annulation of CF3-π-Allyl-Pd Species with Isatic Acids for Direct Access to 3-Trifluoroethyl-4-carboxylate Quinolines. (PubMed, Org Lett) - "In addition, a one-pot protocol enables efficient conversion of the annulation products into 3-trifluoroethyl-4-amido quinolines under the same reaction conditions. The synthetic versatility of this strategy is further demonstrated through the one-pot preparation of a trifluoroethyl analogue of brequinar, as well as the streamlined synthesis of trifluoroethylated analogues of bioactive scaffolds."

Journal

Mechanistic deconvolution reveals DHODH as the key target of the KDM4 inhibitor QC6352 (LCC 2026) - "We discovered that Zavondemstat, the clinical derivative of QC6352, antiproliferative efficacy is likely due to DHODH inhibition, and has even greater potency than other extensively studied DHODH inhibitors including brequinar and BAY2402234. Thus, this discovery has profound implications on future clinical trials using Zavondemstat"

Brain Cancer • Glioblastoma • Solid Tumor

BCOR mutations define a therapeutic vulnerability to DHODH Inhibition in acute myeloid leukemia. (PubMed, Ann Hematol) - "We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. Rather, DHODH's role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL6 • BCOR