Discovery of PG545: a highly potent and simultaneous inhibitor of angiogenesis, tumor growth, and metastasis

J Med Chem. 2012 Apr 26;55(8):3804-13. doi: 10.1021/jm201708h. Epub 2012 Apr 13.


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.

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / therapeutic use*
  • Fibroblast Growth Factor 1 / metabolism
  • Fibroblast Growth Factor 2 / metabolism
  • Glucuronidase / antagonists & inhibitors*
  • Heparitin Sulfate / analogs & derivatives*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Neovascularization, Pathologic / drug therapy
  • Saponins / chemical synthesis
  • Saponins / pharmacokinetics
  • Saponins / therapeutic use*
  • Vascular Endothelial Growth Factor A / metabolism


  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • PG 545
  • Saponins
  • Vascular Endothelial Growth Factor A
  • Fibroblast Growth Factor 2
  • Fibroblast Growth Factor 1
  • Heparitin Sulfate
  • heparanase
  • Glucuronidase