orludodstat (BAY2402234) / Bayer - LARVOL DELTA

Recurrent Breast Cancer Cells Depend on De novo Pyrimidine Biosynthesis to Suppress Ferroptosis. (PubMed, bioRxiv) - "Pharmacologic inhibition of the rate-limiting enzyme DHODH with BAY-2402234 selectively impaired the growth of recurrent tumor cells, while primary tumor cells were relatively resistant...Stable isotope tracing and nutrient depletion experiments showed that primary cells can compensate for DHODH inhibition through nucleotide salvage, whereas recurrent cells exhibit impaired salvage capacity, likely due to reduced expression of Slc28 / Slc29 nucleoside transporters. Together, these findings reveal that breast cancer recurrence is associated with increased dependence on de novo pyrimidine synthesis to suppress ferroptosis, highlighting a therapeutically actionable metabolic vulnerability in recurrent disease."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

TP53-dependent antitumor effects of DHODH Inhibition in nasopharyngeal carcinoma. (PubMed, Discov Oncol) - "Importantly, the low mutation rate of TP53 in NPC suggests that BAY2402234 may be particularly effective in this cancer type. These findings provide the first comprehensive evidence that nucleic acid metabolism plays a crucial role in NPC progression and that the targeting of DHODH represents a promising therapeutic strategy, particularly via TP53-dependent mechanisms."

Journal • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • TP53

Uridine Synthesis Is the Metabolic Vulnerability in Relapse-Associated B-ALL Cells with Active Pre-BCR Signaling (ASH 2023) - "To target this dependency, we treated the cells with the dihydroorotate dehydrogenase (DHODH) inhibitor (BAY-2402234), which disrupts a crucial step in uridine synthesis...Together, we found that preBCRhigh B-ALL cells are associated with relapse and are highly energetic, relying uniquely on glucose for survival to fuel the PPP and uridine synthesis. Inhibition of uridine synthesis is a novel strategy to target these treatment resistant and relapse-associated cells."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • ENO1 • LDHA • PFKFB4

TP53 Aberrant B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Are Uniquely Sensitive to a Combination of Pyrimidine De Novo Synthesis Blockade and Replication Checkpoint Inhibition (ASH 2023) - "Preliminary results from in vivo experiments using p53 deficient patient derived xenografts indicate that the combination of Orludodstat and Berzosertib is well tolerated, while significantly delaying leukemic growth (Figure 1 B). ConclusionTogether, our findings suggest that the combined targeting of de novo pyrimidine synthesis and ATR signaling may present a specific and non-genotoxic vulnerability for TP53 aberrant ALL."

Checkpoint inhibition • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • CHEK1 • TP53

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

Akt mitigates ER stress-instigated cardiac dysfunction via regulation of ferroptosis and mitochondrial integrity in a DHODH-dependent manner. (PubMed, Life Sci) - "ER stress-induced myocardial anomalies were reversed by the newly identified PI3K activator triptolide, DHODH activator menaquinone-4 and pyrimidine booster coenzyme Q. In vitro experiment revealed that Akt activation- or triptolide-evoked beneficial responses against tunicamycin-induced cardiomyocyte anomalies were cancelled off by DHODH inhibitor BAY2402234 or ferroptosis inducer erastin. These findings support that chronic Akt activation rescues ER stress-evoked myocardial derangements through DHODH-dependent control of ferroptosis and mitochondrial homeostasis."

Journal • Fibrosis • Immunology • DDIT3 • GPX4 • HSPA5 • SLC7A11

Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors. (PubMed, Cell Rep Med) - "Treatment of MRT tumoroids with de novo nucleotide synthesis inhibitors methotrexate (MTX) and BAY-2402234 lowers nucleotide levels in MRT tumoroids and induces apoptosis. Lastly, we demonstrate in vivo efficacy of MTX in MRT patient-derived xenograft (PDX) mouse models. Our study reveals nucleotide biosynthesis as an MRT-specific metabolic vulnerability, which can ultimately lead to better treatment options for children suffering from this lethal pediatric malignancy."

Journal • Genito-urinary Cancer • Kidney Cancer • Oncology • Pediatrics • Renal Cell Carcinoma • Rhabdoid Tumor • Sarcoma • Solid Tumor

Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment. (PubMed, Metabolites) - "Furthermore, BAY2402234 reduced the abundance of signaling lipid species in EGFRWT glioblastoma. This study elucidates genetic mutation-specific metabolic plasticity and efficacy in glioblastoma cells in response to drug treatment, offering insights into therapeutic avenues for precision medicine approaches."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Metabolic Disorders • Oncology • Solid Tumor

Discovery and development of HOSU-53 as a potential best-in-class DHODH inhibitor for treating cancer (ACS-Fall 2024) - "Initial hits were generated by undergraduate students at Hendrix College using the brequinar scaffold (h-DHODH IC50 = 1.8 nM; AML MOLM-13 cellular avg...Head-to-head comparison using an AML MOLM-13 in vivo model validated that HOSU-53 (median survival of 63 days vs. 17 days for vehicle control) provided superior survival benefit over the lead clinical comparator BAY2402234 (median survival of 51 days, h-DHDOH IC50 = 0.5 nM; AML MOLM-13 cellular IC50 = 1.5 nM)...A first-in-human, Phase I clinical trial in solid and hematological malignancies is expected to start in the second half of 2024. This collaboration to discover and develop HOSU-53 is a true “bench-to-bedside” story that is all too often elusive in academia."

Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Lung Cancer • Lymphoma • Melanoma • Multiple Myeloma • Oncology • Small Cell Lung Cancer • Solid Tumor

Classical swine fever virus non-structural protein 4A recruits dihydroorotate dehydrogenase to facilitate viral replication. (PubMed, J Virol) - "In this study, three specific DHODH inhibitors, including DHODH-IN-16, BAY-2402234, and Brequinar were found to strongly suppress classical swine fever virus (CSFV) replication. Moreover, NS4A exhibited a strong interaction with DHODH, enhancing its activity to promote efficient CSFV replication. In conclusion, our findings enhance the understanding of the pyrimidine synthesis in CSFV infection and expand the novel functions of CSFV NS4A in viral replication, providing a reference for further exploration of antiviral targets against CSFV."

Journal • Infectious Disease • STAT1

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

Pivotal role of dihydroorotate dehydrogenase as a therapeutic target in adult T-cell leukemia. (PubMed, Eur J Haematol) - "These findings highlight DHODH as a potential therapeutic target for treating ATL."

Journal • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • CCNA2 • CDK2 • DHODH • MYC • NFKBIA • PTEN

De novo pyrimidine synthesis is a druggable vulnerability for chemotherapy resistant nasopharyngeal carcinoma with wild type IDH1 (AACR 2024) - "DHODH inhibitor, BAY2402234 significantly sensitized NPC cells to gemcitabine plus cisplatin chemotherapy. Collectively, these results reveal that wtIDH1-induced increase in de novo pyrimidine nucleotide represents a metabolic vulnerability that can be exploited pharmacologically, highlighting BAY2402234 as a promising strategy to enhance the efficacy of chemotherapy against NPC."

Nasopharyngeal Carcinoma • Oncology • Solid Tumor • ALKBH5 • IDH1

DHODH inhibition represents a therapeutic strategy and improves abiraterone treatment in castration-resistant prostate cancer. (PubMed, Oncogene) - "However, the combination treatment with BAY2402234 and abiraterone decreased intratumoral testosterone levels and induced apoptosis, which inhibited the growth of CWR22Rv1 xenograft tumors and patient-derived xenograft organoids. Taken together, these results establish DHODH as a key player in CRPC and as a potential therapeutic target for advanced prostate cancer."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • DHODH

Cyclin D1 extensively reprograms metabolism to support biosynthetic pathways in hepatocytes. (PubMed, J Biol Chem) - "Pharmacologic inhibition of Cdk4 along with the downstream pyrimidine synthesis enzyme dihydroorotate dehydrogenase synergistically inhibits proliferation and survival of hepatocellular carcinoma cells. These studies demonstrate that cyclin D1 promotes a broad network of biosynthetic pathways in hepatocytes, and this model may provide insights into potential metabolic vulnerabilities in cancer cells."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CCND1 • CDK4 • GAPDH

A potential combinatorial treatment strategy to overcome olaparib resistance in high-grade ovarian cancer (AACR 2023) - "However, in our study, OSU-03012 did not similarly affect cell viability and phenotype on ovarian cancer cell lines as a DHODH inhibitor BAY2402234. Altogether, we identified a potential non-cancer drug for ovarian cancer treatment and to overcome Olaparib resistance. A multidisciplinary approach highlights the importance of drug target profiling and sensitivity signatures scoring to improve treatment stratification."

Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRCA • BRCA1 • BRCA2 • COL3A1 • PDPK1 • PTPRZ1 • TP53

[VIRTUAL] Activity of DHODH inhibitor BAY2402234 in subcutaneous and intracranial models of SCLC (AACR 2021) - P1 | "The results of this investigation confirm and extend previous preclinical results and indicate that BAY2402234 may represent a novel treatment for SCLC, including patients with brain metastases.RESTRICTED"

Acute Myelogenous Leukemia • Brain Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • RB1

Discovery of BAY 2402234 by phenotypic screening: A human Dihydroorotate Dehydrogenase (DHODH) inhibitor in clinical trials for the treatment of myeloid malignancies (AACR 2019) - P1; "A clinical phase I study has been initiated in patients with myeloid malignancies. (NCT03404726)"

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lung Cancer • Oncology • Thoracic Cancer

BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of diffuse large B-cell lymphoma (DLBCL) (AACR 2019) - P1; "In vivo, BAY 2402234 exhibits strong in vivo anti-tumor efficacy in monotherapy in subcutaneous models derived from patient-derived xenograft (PDX) and cell lines representing various DLBCL subtypes, including GCB and ABC. Dose dependent target engagement and drug exposure of BAY 2402234 could be observed by increases in plasma dihydroorotate levels and unbound plasma drug levels after treatment with the inhibitor.Based on preclinical data presented herein we plan to start clinical investigations of BAY 2402234 in patients with DLBCL in early 2019."

Preclinical • Acute Myelogenous Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of colorectal carcinomas (AACR 2019) - P1; "To elucidate the mode of action of BAY 2402234 in CRC we analyzed transcriptomic changes in CRC PDX models in vivo after single treatment with BAY 2402234, and identified several hundred differentially regulated genes at early time points. These in vivo PDX models were also used to explore potential effects of BAY 2402234 treatment on a large panel of metabolites.These preclinical results support the clinical evaluation of BAY 2402234 in patients with CRC, and such a clinical study is planned for early in 2019."

Preclinical • Acute Myelogenous Leukemia • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Identifying Mechanisms of Resistance to DHODH Inhibition in Cancer (ASH 2022) - "Finally, the screens identified several genes whose upregulation sensitized cells to BAY 2402234, including the urokinase receptor PLAUR, the adaptor protein BCAR3, the scaffold protein SHOC2, and the deoxynucleoside phosphohydrolase SAMHD1. Studies are currently underway to validate the results of the CRISPRa screens and elucidate the mechanisms by which the candidate resistance genes help cells to bypass their requirement for DHODH activity."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • DHODH • SLC29A1 • SLC4A1

Abandoned Bayer Drug Shows Preclinical Promise for Childhood Brain Tumors (BioSpace) - "New research out of McMaster University found a recently abandoned Bayer compound halted the growth of an aggressive form of pediatric medulloblastoma in mouse models.... All three teams utilized BAY2402234 to inhibit DHODH for three different kinds of brain cancers, and all signs point to it being a promising approach to stopping brain tumor growth....In the lab, Gwynne observed how gaunt and sickly the mice treated with chemo and radiation were, as is typical in these studies. In stark contrast, the mice treated with the Bayer compound were 'running around the cage happy and healthy.' Those mice also outlived the mice receiving traditional treatments....'This single agent DHODH inhibitor was as effective as current standard of care in this mouse model without the side effects of the mice becoming really, really sick and getting really, really skinny like they normally do,' Gwynne said. Due to the low-toxicity profile, Singh said a Phase I clinical trial is the next logical step."

Preclinical • Brain Cancer • CNS Tumor • Medulloblastoma • Oncology • Solid Tumor

DHODH inhibition impedes glioma stem cell proliferation, induces DNA damage, and prolongs survival in orthotopic glioblastoma xenografts. (PubMed, Oncogene) - "When dosed daily by oral gavage, BAY2402234 significantly impaired the growth of two different intracranial human glioblastoma xenograft models in mice. Given this observed efficacy and the previously established safety profiles in preclinical animal models and human clinical trials, the clinical testing of BAY2402234 in patients with primary glioblastoma that lacks EGFR amplification is warranted."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Immunology • Oncology • Solid Tumor • EGFR

De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma. (PubMed, Cancer Cell) - "We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation."

Journal • Astrocytoma • Brain Cancer • Glioma • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • IDH1

A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma. (PubMed, Cancer Cell) - "A clinical stage inhibitor of DHODH (rate-limiting enzyme in the de novo pathway) diminishes uridine-5'-phosphate (UMP) pools, generates DNA damage, and induces apoptosis through suppression of replication forks-an "on-target" effect, as shown by uridine rescue. Matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in the brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo, and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs."

Journal • Brain Cancer • CNS Disorders • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Immunology • Oncology • Pediatrics • Psychiatry • Solid Tumor