Discovery of PG545: a highly potent and simultaneous inhibitor of angiogenesis, tumor growth, and metastasis
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 inhib...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
March 29, 2012
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| In: |
Journal of medicinal chemistry
Year: 2012, Volume: 55, Issue: 8, Pages: 3804-3813 |
| ISSN: | 1520-4804 |
| DOI: | 10.1021/jm201708h |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1021/jm201708h
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| Author Notes: | Vito Ferro, Ligong Liu, Ken D. Johnstone, Norbert Wimmer, Tomislav Karoli, Paul Handley, Jessica Rowley, Keith Dredge, Cai Ping Li, Edward Hammond, Kat Davis, Laura Sarimaa, Job Harenberg, and Ian Bytheway |
| Summary: | 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 3β-cholestanyl 2,3,4,6-tetra-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-β-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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| Item Description: | Gesehen am 21.09.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1520-4804 |
| DOI: | 10.1021/jm201708h |