Supplementary Figures S1-S7; Supplementary Tables S1-S7; and Supplementary Materials and Methods from Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties
Supplementary Figures S1-S7: Supplementary Figure S1 shows chemical Synthesis and biological characterization of PTC299. Supplementary Figure S2 shows generation and characterization of PTC299-resistant HT1080 cells. Supplementary Figure 3 shows that PTC299 interacts with and inhibits the activity of DHODH. Supplementary Figure S4 shows that PTC299 inhibits de novo UMP production in both sensitive and insensitive cell lines. Supplementary Figure S5 shows that PTC299 has broad activity against leukemia in vitro and in vivo. Supplementary Figure S6 shows
that PTC299 inhibits production of VEGF protein in tumor cells more potently than does brequinar or teriflunomide.
Supplementary Figure S7 shows the comparison of GSK983 and PTC299 in pharmacokinetic study in mice; Supplementary Tables S1-S7: Supplementary Table S1 shows the information on the source of cells and when they were obtained. Supplementary Table S2 shows that the metabolism of 15N-glutamine in cells treated with PTC299 is similar to that measured in cells treated with brequinar, a known DHODH inhibitor. Supplementary Table S3 shows the summary of enriched proteins identified in PTC299 pull-down samples. Supplementary Table S4 shows PTC299 species selectivity: inhibition of de novo UMP. Supplementary Table S5 shows the preclinical safety profile of PTC299. Supplementary Table S6 shows the demographic information for patients in the NF-2 clinical trial. Supplementary Table S7 shows the differences in expression of genes related to pyrimidine nucleotide synthesis and salvage pathway in hematopoietic cancers versus solid tumors.