Open AccessPS1004 PTC299 IS A NOVEL DHODH INHIBITOR FOR USE IN TREATMENT OF AML
Author(s) -
Weetall M.,
Sheedy J.,
Furia B.,
Trotta C.,
Baird J.,
O’Mara E.,
Spiegel R.,
O’Keefe K.,
SmalleraBirns I.,
Borthakur G.,
Kojima K.,
Amitkumar P.
Publication year - 2019
Publication title -
hemasphere
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.677
H-Index - 11
ISSN - 2572-9241
DOI - 10.1097/01.hs9.0000562312.96473.46
Subject(s) - general partnership , business , myeloid leukemia , medicine , big data , public relations , family medicine , finance , political science , computer science , cancer research , data mining
Background: PTC299 is an inhibitor of dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme for de novo pyrimidine nucleotide synthesis that had previously been in clinical trials for treatment of solid tumors. 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 pyrimidine nucleotides from the salvage pathway. Rapidly proliferating cells, however, are dependent on the de novo synthesis of pyrimidine nucleotides. Aims: The goal of these studies was to identify the mechanism by which PTC299 inhibits leukemia cell proliferation and to demonstrate efficacy in a range of cell and mouse models of leukemia. Methods: In vitro studies utilized fresh blood from AML patients that were treated ex vivo with PTC299 and analyzed by flow cytometry. In vivo were done using mouse models of AML. Results: In vitro, AML cells differentiated as shown by increased monocyte markers (e.g. CD14) or showed reduced viability. Consistent with the activity observed in vitro, PTC299 reduced the growth of leukemia cells in mouse models using human cell lines or patient‐derived xenografts (PDX models). When combined with cytotoxic agents and other therapeutics used in treatment of AML, PTC299 enhanced activity in multiple mouse models of leukemia. Summary/Conclusion: The favorable pharmaceutical properties of PTC299 together with an extensive PH1/2 clinical experience in solid tumors with PTC299 make this a promising agent for treatment of leukemia. Based on these data, a Ph1b trial in AML has been initiated at multiple sites in the US.