Title |
Discovery of PG545: A Highly Potent and Simultaneous Inhibitor of Angiogenesis, Tumor Growth, and Metastasis
|
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Published in |
Journal of Medicinal Chemistry, April 2012
|
DOI | 10.1021/jm201708h |
Pubmed ID | |
Authors |
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, Ian Bytheway |
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 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 1 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 1 | 1% |
Germany | 1 | 1% |
Australia | 1 | 1% |
Unknown | 64 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 20 | 30% |
Researcher | 13 | 19% |
Other | 5 | 7% |
Student > Master | 5 | 7% |
Student > Bachelor | 4 | 6% |
Other | 10 | 15% |
Unknown | 10 | 15% |
Readers by discipline | Count | As % |
---|---|---|
Chemistry | 23 | 34% |
Biochemistry, Genetics and Molecular Biology | 11 | 16% |
Agricultural and Biological Sciences | 5 | 7% |
Medicine and Dentistry | 5 | 7% |
Immunology and Microbiology | 3 | 4% |
Other | 7 | 10% |
Unknown | 13 | 19% |