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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Discovery of PG545: A highly potent and simultaneous inhibitor of angiogenesis, tumor growth, and metastasis
Journal of Medicinal Chemistry, Volume 55, No. 8, Year 2012
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Description
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. © 2012 American Chemical Society.
Authors & Co-Authors
Ferro, Vito
Australia, Brisbane
Progen Pharmaceuticals Limited
Australia, Brisbane
The University of Queensland
Liu, Ligong
Australia, Brisbane
Progen Pharmaceuticals Limited
Australia, Brisbane
The University of Queensland
Johnstone, Ken D.
Australia, Brisbane
Progen Pharmaceuticals Limited
Botswana, Kanye
National Food Technology Research Centre
Wimmer, Norbert
Australia, Brisbane
Progen Pharmaceuticals Limited
Australia, Brisbane
Alchemia Limited
Karoli, Tomislav
Australia, Brisbane
Progen Pharmaceuticals Limited
Australia, Brisbane
The University of Queensland
Handley, Paul N.
Australia, Brisbane
Progen Pharmaceuticals Limited
Rowley, Jessica A.
Australia, Brisbane
Progen Pharmaceuticals Limited
Dredge, Keith
Australia, Brisbane
Progen Pharmaceuticals Limited
Li, Caiping
Australia, Brisbane
Progen Pharmaceuticals Limited
Australia, Coopers Plains
Public Health Microbiology Communicable Diseases Forensic and Scientific Services
Hammond, Edward
Australia, Brisbane
Progen Pharmaceuticals Limited
Davis, Kat
Australia, Brisbane
Progen Pharmaceuticals Limited
Sarimaa, Laura
Australia, Brisbane
Progen Pharmaceuticals Limited
Australia, Brisbane
Griffith University
Harenberg, Job F.
Germany, Heidelberg
Universität Heidelberg
Bytheway, Ian R.
Australia, Brisbane
Progen Pharmaceuticals Limited
Statistics
Citations: 108
Authors: 14
Affiliations: 7
Identifiers
Doi:
10.1021/jm201708h
ISSN:
00222623
e-ISSN:
15204804
Research Areas
Cancer