Abstract
PTC299 was identified in a phenotypic high through put screen as an inhibitor of VEGFA mRNA translation and had been in clinical development for solid tumors. Here we demonstrate that PTC299 inhibits dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme for de novo pyrimidine nucleotide synthesis. Our results demonstrate an unexpected role for pyrimidine nucleotide levels in the regulation of VEGF mRNA translation. Pyrimidine nucleotides can be generated either by de novo synthesis or the salvage pathway in which pyrimidine nucleotides are obtained from the diet. Resting cells typically acquire adequate levels of pyrimidine nucleotides from the salvage pathway. Rapidly proliferating cells, however, are dependent on the de novo synthesis of pyrimidine nucleotides.To identify cancer cell types that are sensitive to PTC299, a panel of 240 tumor cell lines was tested against which the concentration of compound required to reduce cell viability by 50% (CC50) was determined. Overall, the viability of 18% of cells from solid tumor(34/184) and ~57% of cells from hematologic malignancies (32/56) was reduced with a CC50 of 2 µM or less. Fresh blood from AML patients was treated ex vivo with PTC299 and analyzed by flow cytometry. In these samples, AML cells differentiated as shown by increased monocyte markers (e.g. CD14) or showed reduced viability as shown by a reduction in the blast population. PTC299 reduced the growth of leukemia cells in mouse models using human cell lines or patient-derived xenografts (PDX models). In combination, PTC299 enhanced the activity of various cytotoxic agents in animal models of solid tumor and leukemia. Consistent with the activity of PTC299 as a DHODH inhibitor, patients treated with PTC299 in clinical studies showed increased levels of dihydroorotate, the substrate of DHODH, were observed in serum samples from PTC299-treated patientsIn summary, we describe an unanticipated link between the inhibition of DHODH by PTC299 and subsequent translation of the mRNA for VEGFA, a key stress-induced regulator of angiogenesis. The integration between biological pathways such as pyrimidine nucleotide synthesis and protein translation contributes to the basic understanding of the strategies by which leukemia cells sustain rapid proliferation. Importantly, its favorable pharmaceutical properties together with its extensive PH1/2 clinical experience make PTC299 a promising agent for treatment of leukemia DisclosuresCao:PTC Therapeutics: Employment. Branstrom:PTC Therapeutics: Employment. Baird:PTC Therapeutics: Employment. Trotta:PTC Therapeutics: Employment. Colacino:PTC Therapeutics: Employment. Santaguida:Notable Laboratories: Consultancy. Heiser:Notable Laboratories: Consultancy. Ma:PTC Therapeutics: Employment. Peltz:PTC Therapeutics: Employment. O'Mara:PTC Therapeutics: Employment. Spiegel:PTC Therapeutics: Consultancy. Weetall:PTC Therapeutics: Employment.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.