GSE121266 Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties

Contributors : Liangxian Cao ; Marla Weetall ; Christopher Trotta ; Katherine Cintron ; Jiyuan Ma ; Min J Kim ; Bansri Furia ; Charles Romfo ; Jason D Graci ; Wencheng Li ; Joshua Du ; Josephine Sheedy ; Jean Hedrick ; Nicole Risher ; Shirley Yeh ; Hongyan Qi ; Tamil Arasu ; Seongwoo Hwang ; William Lennox ; Ronald Kong ; Janet Petruska ; Young-Choon Moon ; John Babiak ; Thomas W Davis ; Allan Jacobson ; Neil G Almstead ; Art Branstrom ; Joseph M Colacino ; Stuart W PeltzSeries Type : Expression profiling by arrayOrganism : Homo sapiensPTC299 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 nucleo...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Homo sapiens Source Type: research