biostudies-literatureUnknown3(3)Eriksen-Gjerstad MMantle cell lymphoma (MCL) is a non-Hodgkin lymphoma that remains incurable with the treatment options available today. In the present study, we have identified the dihydroorotate dehydrogenase (DHODH), an essential enzyme for the <i>de novo </i>biosynthesis of pyrimidine-based nucleotides, to be overexpressed in MCL in comparison to healthy peripheral blood mononuclear cells (PBMC). In vitro inhibition of the DHODH activity using a newly developed DHODH inhibitor, namely (<i>R</i>)-HZ05, can induce MCL cell death in the nanomolar range independently than the P53 status of the investigated cell lines. Moreover, the combination of (<i>R</i>)-HZ05 with tyrosine kinase inhibitor shows the synergistic activity on cell death. Pre-clinical investigation on the efficacy of (<i>R</i>)-HZ05 shows tEJHaem913-918https://www.ebi.ac.uk/biostudies/studies/S-EPMC9422018biostudies-literatureDihydroorotate dehydrogenase inhibition acts synergistically with tyrosine kinase inhibitors to induce apoptosis of mantle cell lymphoma cells.PMC9422018Gelebart PTveit Karlsen ILocke FMc Cormack EBaran-Marszak FPastor-Fernandez AEriksen-Gjerstad MLadds MFandalyuk ZPapp BBenjaminsen SfalseDihydroorotate dehydrogenase inhibition acts synergistically with tyrosine kinase inhibitors to induce apoptosis of mantle cell lymphoma cells.Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma that remains incurable with the treatment options available today. In the present study, we have identified the dihydroorotate dehydrogenase (DHODH), an essential enzyme for the <i>de novo </i>biosynthesis of pyrimidine-based nucleotides, to be overexpressed in MCL in comparison to healthy peripheral blood mononuclear cells (PBMC). In vitro inhibition of the DHODH activity using a newly developed DHODH inhibitor, namely (<i>R</i>)-HZ05, can induce MCL cell death in the nanomolar range independently than the P53 status of the investigated cell lines. Moreover, the combination of (<i>R</i>)-HZ05 with tyrosine kinase inhibitor shows the synergistic activity on cell death. Pre-clinical investigation on the efficacy of (<i>R</i>)-HZ05 shows t2022-01-01T00:00:00Z2022 Aug2025-04-05T12:10:50.937Z2025-04-05T12:10:50.937ZS-EPMC94220183605106610.1002/jha2.434