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

An essential link between pyrimidine synthesis and ferroptosis suppression in erythroid differentiation (ASH 2025) - "Giemsa staining of sorted erythroid precursors in the presence of the DHODHinhibitor brequinar revealed a larger proportion of less differentiated basophilic to the moredifferentiated polychromatic erythroblasts compared to vehicle control. Co-treatment with theferroptosis inhibitor liproxstatin-1 partially rescued this erythroid differentiation block resulting in alarger proportion of polychromatic erythroblasts...Our resultsdemonstrate that the differentiation of erythroid progenitors and precursors depends on thesuppression of ferroptosis. We further reveal a novel tight link between pyrimidine metabolism andferroptosis defense in erythropoiesis and uncover distinct adaptive plasticity of de novo and salvagenucleotide synthesis during erythroid differentiation, which, in the long-term, will open new avenues totreat anemia."

Anemia • Aplastic Anemia • CD34 • GPX4

DHODH-driven pyrimidine metabolism is a targetable vulnerability in myeloproliferative neoplasms (ASH 2025) - "Protein-level validationconfirmed increased expression of phosphorylated CAD (pCAD) and dihydroorotate dehydrogenase(DHODH), two key enzymes regulating the rate-limiting steps in de novo pyrimidine synthesis.Mechanistically, we identified a STAT5–MYC–DHODH regulatory axis: pharmacologic inhibition of STAT5or MYC reduced DHODH expression, and ChIP-qPCR analysis demonstrated direct MYC binding at theDHODH promoter in JAK2-mutant cells.To evaluate the therapeutic relevance of this metabolic dependency, we treated Jak2V617F knock-in micewith Brequinar, a clinically investigated DHODH inhibitor, either alone or in combination with ruxolitinib,a JAK1/2 inhibitor approved for MPNs. We identify DHODH as a criticaldownstream effector in this metabolic program, transcriptionally regulated via the STAT5–MYC axis.Pharmacologic targeting of DHODH disrupts pyrimidine metabolism, suppresses aberranthematopoiesis, and enhances the efficacy of JAK inhibition in both murine and human..."

Myeloproliferative Neoplasm • CD34 • DHODH • KRAS • STAT5

Pyrimidine Starvation Is a Targetable Cancer Vulnerability: Mechanisms of Nucleotide Homeostasis (ASH 2023) - " Treatment of leukemia cells with brequinar blocked de novo synthesis and led to the rapid depletion of intracellular pyrimidines... We hypothesized that the transformation from normal to malignant cell is accompanied by changes in nucleotide metabolism that render the transformed cells more reliant on de novo synthesis, establishing a metabolic vulnerability (and inherent therapeutic window) in the use of DHODH inhibitors. Our work confirms that leukemic blasts differ in their dependence on de novo nucleotide synthesis and its ability to garner nucleotides via salvage or autophagy pathways. This balance appears to be disturbed in the setting of malignancy such that leukemic cells are empirically more sensitive to treatment targeting pyrimidine synthesis."

Acute Myelogenous Leukemia • Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Glioma • Hematological Malignancies • Leukemia • Lung Cancer • Neuroblastoma • Oncology • Pancreatic Cancer • Small Cell Lung Cancer • Solid Tumor • CD34 • GLI2

DHODH Inhibitor Therapy for the Treatment of T-ALL Spares the Developing Thymus (ASH 2023) - "These mice were treated with the small molecule DHODHi brequinar (BRQ) 50 mg/kg every 72 hours, and were paired with age and gender-matched controls at each time point of analysis...A defective or less efficient process of extracellular salvage could help to explain this cell line's unusual dependence on de novo nucleotide synthesis. Overall, we hope that these findings will pave the way for additional preclinical studies and eventually clinical trials for pediatric patients with T-cell disease."

Brain Cancer • Breast Cancer • CNS Tumor • Gastrointestinal Cancer • Glioblastoma • Hematological Malignancies • Leukemia • Neuroblastoma • Oncology • Pancreatic Cancer • Pediatrics • Solid Tumor • T Acute Lymphoblastic Leukemia

Hnrnpc and m6a RNA Methylation Control Oncogenic Transcription and Metabolism in T-Cell Leukemia (ASH 2024) - "The use of the FTO inhibitors CS1 (bisantrene) and CS2 (brequinar, Su R. et al., Cancer Cell, 2020) for the treatment of cell lines, patient samples ex vivo, and a xenograft T-ALL model showed high efficacy of the drugs in inhibiting T-ALL. Combining FTO inhibitors with dexamethasone and other chemotherapeutic agents demonstrated synergy in inhibiting T-ALL. These findings indicate that T-ALL exhibits dysregulated RNA methylation and demonstrate the potential of targeting HNRNPC and FTO as therapeutic strategies in T-ALL."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • HMGCS1 • HNRNPC • METTL3

Epitranscriptomic reprogramming and enzalutamide resistance in prostate cancer (PCF 2025) - "Novel small molecule inhibitors of METTL3 are in phase I clinical trials and derivatives of drugs and candidates such as entacapone, meclofenamic acid, brequinar and bisantrene that inhibit FTO are in development. Targeting m6A and its regulators may provide a novel mechanism to alter androgen and androgen receptor signalling offering therapeutic potential on its own and in combination with other therapies including enzalutamide. Funding Acknowledgements:This work has been funded by Prostate Cancer Foundation and John Black Charitable Foundation Challenge Awards: 20CHAL04 and 22CHAL11; and Prostate Cancer UK Research Innovation Award RIA21-ST2- 002; the University of Nottingham, unrestricted gifts from the Stanyard, Moody and Kenyon families to support prostate cancer research and the BBSRC doctoral training program award: BB/I024291/1. Conflicts of Interest Disclosure Statement: No conflicts of interest to disclose."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ALKBH5 • METTL3

NK-A 17E-233I: a novel competitive inhibitor of human dihydroorotate dehydrogenase (DHODH) for cancer therapy. (PubMed, J Exp Clin Cancer Res) - "Unlike Brequinar, NK-A 17E-233I preserves mitochondrial respiration via complexes I and II and maintains ATP-linked basal respiration, avoiding the impairment of the electron transport chain (ETC). Our findings imply the aptitude of NK-A 17E-233I as a novel competitive inhibitor of human DHODH, representing a significant advancement in this field since the 1990s."

Journal • Oncology

Metabolic Dependency on De Novo Pyrimidine Synthesis is a Targetable Vulnerability in Platinum Resistant Ovarian Cancer. (PubMed, Cancer Res) - "Targeting this pathway using brequinar (BRQ), an inhibitor of the key enzyme dihydroorotate dehydrogenase (DHODH), decreased cell viability, delayed G2/M cell cycle progression, and altered expression of genes related to mitochondrial electron transport in resistant cells. In cell line-derived and patient-derived xenograft models, BRQ attenuated the growth of cisplatin resistant ovarian tumors and enhanced the inhibitory effects of carboplatin. Together, these results identify metabolic reprogramming in cisplatin resistant ovarian cancer that induces an acquired dependency on de novo pyrimidine synthesis, which can be targeted to sensitize tumors to chemotherapy."

Journal • Platinum resistant • Oncology • Ovarian Cancer • Solid Tumor

Integrative Spatial Analysis Reveals Ferroptosis Heterogeneity and Novel Therapeutic Vulnerabilities in Small Cell Lung Cancer (IASLC-WCLC 2025) - "Pharmacological inhibition of DHODH using Brequinar selectively suppressed proliferation and induced ferroptosis in MR SCLC cell lines...Conclusions : The ferroptosis heterogeneity across SCLC emphasizes the need to map individual patient landscapes to develop personalized treatment strategies. Our findings provide critical insights into SCLC biology and serve as a valuable resource for future molecular investigations and therapeutic exploration."

Heterogeneity • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ASCL1

Calcium Phosphate-Mineralized Nanoplatform for Enhanced Ferroptosis and Synergistic Anti-PDL1 Therapy in Triple-Negative Breast Cancer Through Multi-Pathway Targeting. (PubMed, Acta Biomater) - "To overcome these limitations, we have engineered a calcium phosphate-mineralized ferroptosis inducer nanoplatform, termed Lf-PEG-CaP@iFSP1-Brequinar-Erastin-Fe3+-TA (LP-CaP@iBEFT), designed to augment ferroptosis by simultaneously targeting three key pathways: glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and dihydroorotate dehydrogenase (DHODH). This approach effectively dismantles the "triple defense" mechanism that tumor cells employ to resist ferroptosis. In addition, this nanoplatform synergizes with anti-PD-L1 immune checkpoint blockade, enhancing the T cell-mediated destruction of tumor cells."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AIFM2 • GPX4

De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer. (PubMed, Nat Commun) - "The combination of DHODH inhibition with Brequinar and BCL-XL degradation by DT2216, a proteolysis targeting chimera (PROTAC), significantly inhibits PDAC tumor growth. These data define mechanisms of adaptation to DHODHi and support combination therapy targeting BCL-XL in PDAC."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • BCL2L1 • KRAS

Design, synthesis and biological evaluation of N-pyridinyl ureidobenzenesulfonates and their hydrochloride salts as novel water-soluble dihydroorotate dehydrogenase inhibitors inducing differentiation of acute myeloid leukemia cells. (PubMed, RSC Med Chem) - "In addition, molecular docking studies show their stable binding modes in the brequinar-binding site of DHODH...Finally, they exhibit metabolic stability with half-lives varying from 57 to 216 min in rodent and human liver microsomes. Our study highlights that the new PYRUB-SO salts improve the water solubility of this new family of DHODH inhibitors while maintaining their biological activity."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD14 • ITGAM • NDUFA2

Induction of ferroptosis and senescence in epithelial ovarian cancer cell line: Implications of targeted therapeutic strategies (EACR 2025) - "This study investigates the effects of senescence and ferroptosis inducers on two distinct epithelial ovarian cancer (EOC) cell lines, SKOV-3 and OVCAR-3, using qPCR to assess the expression of various biomarkers.Material and SKOV-3 and OVCAR-3 EOC cell lines were treated with ferroptosis inducers (RSL3, Erastin, FSP1i, Brequinar) and senescence inducers (Etoposide, Olaparib, Carboplatin, Cisplatin). This study highlights the potential of targeting both senescence and ferroptosis in epithelial ovarian cancer. Ferroptosis-related biomarkers, such as NCOA4 and CP, were modulated independently of cell line, indicating a common response to ferroptosis induction. Senescence was more cell line-dependent, with CDKN1A and CDKN2A serving as markers of senescence induction in OVCAR-3."

Preclinical • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CDKN1A • CDKN2A • CXCL8 • IL6 • NCOA4

Pan-cancer analysis of signaling pathways regulatory connection with pyrimidine metabolism and its chemoresistance role (EACR 2025) - "In addition, PyMet inhibition was explored for the synergistic activity with commonly used chemotherapeutic drugs such as cisplatin and doxorubicin using cell lines and mouse derived KrasG12D p53Δ/Δ lung tumor organoids to improve chemosensitivity of the drugs.Result and Pan-cancer analysis with pathway-based approach has identified a strong inter-dependency of regulatory connections of PyMet including TERT, MTOR, DAX1, HOXA1, TP53 and TNC which in turn was tightly linked to chemoresistance. The study highlights the complex signaling and metabolic cascades governing pyrimidine metabolism and its role in chemoresistance, and thereby providing an effective tool for advancing PyMet targeting strategy in cancer. The analysis as an accessible resource is available at: www.pype.compbio.sdu.dk"

Pan tumor • Lung Cancer • Oncology • Solid Tumor • KRAS • TP53 • TYMS

Nucleotide imbalance sensed by p53 leads to an upregulation of pyrimidine salvage transporter hCNT1 (EACR 2025) - "In order to induce DNA damage or an imbalance on nucleotide pools, cells were subjected to different treatments, including Etoposide or Brequinar. wtp53 regulates nucleoside salvage pathway transporter hCNT1 expression. Besides, in cell contexts where wtp53 is induced by DNA damage or imbalance of nucleotide pools transcription of hCNT1 is potentiated. However, mtp53 fails to induce hCNT1 expression."

Oncology • NTS • RRM2B

DHODH inhibition overcomes macrophage-mediated resistance to cytarabine in acute myeloid leukemia (AML) (EACR 2025) - "Introduction: The standard induction therapy for acute myeloid leukemia (AML) consists of 7 days of cytarabine (AraC) and 3 days of an anthracycline (the "7+3" regimen). Our study identifies macrophage-derived dC as a novel mediator of AraC resistance in AML. Targeting pyrimidine metabolism in macrophages may provide a strategy to overcome chemoresistance and improve therapeutic outcomes in AML patients."

Late-breaking abstract • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • DCK

Mechanisms of AICAr-Induced Acute Myeloid Leukemia Differentiation: Role of Ribonucleotide Metabolism and Replication Stress (EACR 2025) - "We also found that cytarabine (AraC), a standard chemotherapy agent, promotes differentiation via replication stress and Chk1 activation, a mechanism shared with pyrimidine synthesis inhibitors...Inhibition studies were conducted using COH29 and hydroxyurea (HU) as inhibitors of ribonucleotide reductase (RNR), MK1775 as a Wee1 inhibitor, and siRNA targeting Wee1.Result and Metabolomic analysis revealed that pyrimidine and purine nucleotides were among the most differentially regulated metabolites, decreasing in brequinar- and AICAr-treated samples while increasing in AraC-treated samples... Our findings suggest that ribonucleotide metabolism regulates AML differentiation, with Wee1 and RNR activation occurring downstream of replication stress."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CHEK1 • RRM2

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

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

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

Discovery of a New Class of Thiazolidin-4-one-Based Inhibitors of Human Dihydroorotate Dehydrogenase: Biological Activity Evaluation, Molecular Docking, and Molecular Dynamics. (PubMed, ACS Omega) - "Compared to the cocrystallized structure of the brequinar analogue complex, inhibitors 10 and 16 increased their direct interaction with Ala55...This conclusion provides help for further research into hDHODH inhibitors in the future. This study has promoted the significance of the development of broad-spectrum antiviral drugs."

Journal

Transcriptomic changes and mitochondrial toxicity in response to acute and repeat dose treatment with brequinar in human liver and kidney in vitro models. (PubMed, Toxicol In Vitro) - "Furthermore, brequinar could impair the mitochondrial respiration of RPTEC/TERT1 cells after 24 h. This study provides new insights into the differential responses of PHH and RPTEC/TERT1 cells in response to brequinar exposure and highlights the biological relevance of implementing repeated dosing regimens in in vitro studies."

Journal • Preclinical • Oncology

Combination decoction of Astragalus mongholicus and Salvia miltiorrhiza mitigates pressure-overload cardiac dysfunction by inhibiting multiple ferroptosis pathways. (PubMed, Front Pharmacol) - "Interventions included decoctions of AM and SM (for animal experiments) and medicated serum (for cell experiments), along with specific pathway inhibitors such as erastin, FSP1 inhibitor and brequinar. It shows that the protective effect is strongest through GPX4, followed by FSP1, and weakest through DHODH. These findings provide new insights into the therapeutic mechanisms of this combination of botanical drugs."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • AIFM2 • DHODH • GPX4

Off-Target Inhibition of Human Dihydroorotate Dehydrogenase (hDHODH) Highlights Challenges in the Development of Fat Mass and Obesity-Associated Protein (FTO) Inhibitors. (PubMed, ACS Pharmacol Transl Sci) - "Similarly, the FTO inhibitor CS2 (brequinar), known as one of the most potent hDHODH inhibitors, exhibited FTO-independent antileukemic effects. Uridine supplementation fully rescued leukemia cells from FB23-2 and CS2-induced growth inhibition, but not ZLD115, confirming the inhibition of pyrimidine synthesis as the primary mechanism of action underlying their antileukemic activity. These findings underscore the importance of considering off-target effects on hDHODH in the development of FTO inhibitors to optimize their therapeutic potential and minimize unintended consequences."

Journal • Genetic Disorders • Obesity

A CIA strategy with eminent drug-loading capacities for tumor ferroptosis-gas synergistic therapy. (PubMed, Theranostics) - " Fe2+, β-Lapachone (LAP), brequinar (BQR), or Sorafenib (SOR) was respectively loaded onto Gd poly (acrylic acid) macrochelate (GP), an MRI CA, in the hollow core of nitrite-modified hollow mesoporous organosilica nanoparticles (HMON-SNO). The proposed strategy of CIA with universality was successfully utilized to restrict the aggregation of MRI CAs at high drug loading conditions. The developed FeGP@HMON-SNO with eminent drug loading content were used for tumor ferroptosis-gas synergistic therapy with high efficacy."

Journal • Metabolic Disorders • Oncology