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  • Discovery of PG545: A Highly Potent and Simultaneous Inhibitor of Angiogenesis, Tumor Growth, and Metastasis

    Author(s)
    Ferro, V
    Liu, L
    Johnstone, KD
    Wimmer, N
    Karoli, T
    Handley, P
    Rowley, J
    Dredge, K
    Li, CP
    Hammond, E
    Davis, K
    Sarimaa, L
    Harenberg, J
    Bytheway, I
    Griffith University Author(s)
    Sarimaa, Laura J.
    Rowley, Jessica
    Year published
    2012
    Metadata
    Show full item record
    Abstract
    Increasing the aglycone lipophilicity of a series of polysulfated oligosaccharide glycoside heparan sulfate (HS) mimetics via attachment of a steroid or long chain alkyl group resulted in compounds with significantly improved in vitro and ex vivo antiangiogenic activity. The compounds potently inhibited heparanase and HS-binding angiogenic growth factors and displayed improved antitumor and antimetastatic activity in vivo compared with the earlier series. Preliminary pharmacokinetic analyses also revealed significant increases in half-life following iv dosing, ultimately supporting less frequent dosing regimens in preclinical ...
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    Increasing the aglycone lipophilicity of a series of polysulfated oligosaccharide glycoside heparan sulfate (HS) mimetics via attachment of a steroid or long chain alkyl group resulted in compounds with significantly improved in vitro and ex vivo antiangiogenic activity. The compounds potently inhibited heparanase and HS-binding angiogenic growth factors and displayed improved antitumor and antimetastatic activity in vivo compared with the earlier series. Preliminary pharmacokinetic analyses also revealed significant increases in half-life following iv dosing, ultimately supporting less frequent dosing regimens in preclinical tumor models compared with other HS mimetics. The compounds also displayed only mild anticoagulant activity, a common side effect usually associated with HS mimetics. These efforts led to the identification of 3߭cholestanyl 2,3,4,6-tetra-O-sulfo-a-d-glucopyranosyl-(1?4)-2,3,6-tri-O-sulfo-a-d-glucopyranosyl-(1?4)-2,3,6-tri-O-sulfo-a-d-glucopyranosyl-(1?4)-2,3,6-tri-O-sulfo-߭d-glucopyranoside, tridecasodium salt (PG545, 18) as a clinical candidate. Compound 18 was recently evaluated in a phase I clinical trial in cancer patients.
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    Journal Title
    Journal of Medicinal Chemistry
    Volume
    55
    Issue
    8
    DOI
    https://doi.org/10.1021/jm201708h
    Copyright Statement
    Self-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the authors for more information.
    Subject
    Clinical Pharmacology and Therapeutics
    Medicinal and Biomolecular Chemistry
    Organic Chemistry
    Pharmacology and Pharmaceutical Sciences
    Publication URI
    http://hdl.handle.net/10072/48699
    Collection
    • Journal articles

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