• Login
    View Item 
    •   Home
    • UMass Chan Faculty and Staff Research and Publications
    • UMass Chan Faculty and Researcher Publications
    • View Item
    •   Home
    • UMass Chan Faculty and Staff Research and Publications
    • UMass Chan Faculty and Researcher Publications
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of eScholarship@UMassChanCommunitiesPublication DateAuthorsUMass Chan AffiliationsTitlesDocument TypesKeywordsThis CollectionPublication DateAuthorsUMass Chan AffiliationsTitlesDocument TypesKeywords

    My Account

    LoginRegister

    Help

    AboutSubmission GuidelinesData Deposit PolicySearchingAccessibilityTerms of UseWebsite Migration FAQ

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

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

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Authors
    Cao, Liangxian
    Weetall, Marla
    Trotta, Christopher
    Cintron, Katherine
    Ma, Jiyuan
    Kim, Min Jung
    Furia, Bansri
    Romfo, Charles
    Graci, Jason D
    Li, Wencheng
    Du, Joshua
    Sheedy, Josephine
    Hedrick, Jean
    Risher, Nicole
    Yeh, Shirley
    Qi, Hongyan
    Arasu, Tamil
    Hwang, Seongwoo
    Lennox, William
    Kong, Ronald
    Petruska, Janet
    Moon, Young-Choon
    Babiak, John
    Davis, Thomas W
    Jacobson, Allan
    Almstead, Neil G
    Branstrom, Art
    Colacino, Joseph M
    Peltz, Stuart W
    Show allShow less
    UMass Chan Affiliations
    Microbiology and Physiological Systems
    Document Type
    Journal Article
    Publication Date
    2018-10-23
    
    Metadata
    Show full item record
    Link to Full Text
    https://doi.org/10.1158/1535-7163.mct-18-0863
    Abstract
    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.
    Source
    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 YC, Babiak J, Davis TW, Jacobson A, Almstead NG, Branstrom A, Colacino JM, Peltz SW. Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties. Mol Cancer Ther. 2019 Jan;18(1):3-16. doi: 10.1158/1535-7163.MCT-18-0863. Epub 2018 Oct 23. PMID: 30352802; PMCID: PMC6318026.
    DOI
    10.1158/1535-7163.MCT-18-0863
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/51743
    PubMed ID
    30352802
    Rights
    ©2018 American Association for Cancer Research.
    ae974a485f413a2113503eed53cd6c53
    10.1158/1535-7163.MCT-18-0863
    Scopus Count
    Collections
    UMass Chan Faculty and Researcher Publications

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Lamar Soutter Library, UMass Chan Medical School | 55 Lake Avenue North | Worcester, MA 01655 USA
    Quick Guide | escholarship@umassmed.edu
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.