orludodstat (BAY2402234)

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.

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.

These findings highlight DHODH as a potential therapeutic target for treating ATL.

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.

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.

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.

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.

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.

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.

Functional Assays : RNA interference and inhibitors that selectively target GLS (CB-839), DHODH (Teriflunomide, Leflunomide, Vidofludimus, Brequinar and BAY 2402234) or BRD4 (MZ-1; JQ1; AZD5153; Mivebresib and Birabresib) potently and specifically diminish the clonogenic potential of several SCCHN cell lines. However, none of these treatments induce comparable apoptosis in the ex vivo SCCHN tumour tissue. Conclusion The challenges presented by the tumour microenvironment in diminishing the potential of several promising therapies will have to be characterised further, which is the primary focus of our current studies.