A DHODH inhibitor
AG-636 is a dihydroorotate dehydrogenase (DHODH) inhibitor (IC50 = 17 nM).1 It increases levels of ureidosuccinic acid and DHO, pyrimidine biosynthesis metabolites upstream of DHODH, in a panel of six cell lines when used at a concentration of 1 ?M. AG-636 (100 mg/kg) induces complete tumor stasis in an OCI-Ly19 diffuse large B cell lymphoma (DLBCL) mouse xenograft model and complete tumor regression in a Z-138 ibrutinib-resistant mantle cell lymphoma mouse xenograft model. It also increases DHO levels and reduces pyrimidine levels in Z-138 and JeKo-1 lymphoma mouse xenograft models.
1.McDonald, G., Chubukov, V., Coco, J., et al.Selective vulnerability to pyrimidine starvation in hematologic malignancies revealed by AG-636, a novel clinical-stage inhibitor of dihydroorotate dehydrogenaseMol. Cancer Ther.19(12)2502-2515(2020)
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