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| Status |
Public on Oct 16, 2018 |
| Title |
Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
PTC299 was identified as an inhibitor of VEGFA mRNA translation in a phenotypic screen and evaluated in the clinic for treatment of solid tumors. To guide precision cancer treatment, we performed extensive biological characterization of the activity of PTC299 and demonstrated that inhibition of VEGF production and cell proliferation by PTC299 is linked to a decrease in uridine nucleotides by targeting dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme for de novo pyrimidine nucleotide synthesis. Unlike previously reported DHODH inhibitors that were identified using in vitro enzyme assays, PTC299 is a more potent inhibitor of DHODH in isolated mitochondria suggesting that mitochondrial membrane lipid engagement in the DHODH conformation in situ is required for its optimal activity. PTC299 has broad and potent activity against hematological cancer cells in preclinical models, reflecting a reduced pyrimidine nucleotide salvage pathway in leukemia cells. Archived serum samples from patients treated with PTC299 demonstrated increased levels of dihydroorotate, the substrate of DHODH, indicating target engagement in patients. PTC299 has advantages over previously reported DHODH inhibitors, including greater potency, good oral bioavailability and lack of off-target kinase inhibition and myelosuppression, and thus may be useful for the targeted treatment of hematologic malignancies.
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| Overall design |
Transcriptome profiling of PTC299-resistant and parent HT1080 cells using Affymetrix Human Genome U133 plus 2.0 Array. Four replicates of cells for each cell type were performed.
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| Contributor(s) |
Cao L, Weetall M, Trotta C, Cintron K, Ma J, Kim MJ, Furia B, Romfo C, Graci JD, Li W, Du J, Sheedy J, Hedrick J, Risher N, Yeh S, Qi H, Arasu T, Hwang S, Lennox W, Kong R, Petruska J, Moon Y, Babiak J, Davis TW, Jacobson A, Almstead NG, Branstrom A, Colacino JM, Peltz SW |
| Citation(s) |
30352802 |
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| Submission date |
Oct 15, 2018 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Wencheng Li |
| Organization name |
PTC Therapeutics
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| Street address |
100 Corporate Count
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| City |
South Plainfield |
| State/province |
NJ - New Jersey |
| ZIP/Postal code |
07080 |
| Country |
USA |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA496503 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE121266_RAW.tar |
35.4 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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