American Association for Cancer Research
206336_3_supp_5083793_pg7s1c.xlsx (11.94 MB)

Supplementary Excel file-1 from Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties

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posted on 2023-04-03, 16:06 authored by Liangxian Cao, Marla Weetall, Christopher Trotta, Katherine Cintron, Jiyuan Ma, Min Jung 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. Peltz

contains the raw data from the Microarrays study in the PTC299-resistant HT1080 cells





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 hematologic 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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