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
Year published
2012
Metadata
Show full item recordAbstract
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 ...
View more >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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View more >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
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