title: Discovery of PG545: a highly potent and simultaneous inhibitor of angiogenesis, tumor growth, and metastasis.
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.
authors.affiliation: Drug Design Group, Progen Pharmaceuticals Limited, Brisbane, Queensland 4076, Australia. v.ferro@uq.edu.au
authors.forename: Vito
authors.initials: V
authors.lastname: Ferro
authors.forename: Ligong
authors.initials: L
authors.lastname: Liu
authors.forename: Ken D
authors.initials: KD
authors.lastname: Johnstone
authors.forename: Norbert
authors.initials: N
authors.lastname: Wimmer
authors.forename: Tomislav
authors.initials: T
authors.lastname: Karoli
authors.forename: Paul
authors.initials: P
authors.lastname: Handley
authors.forename: Jessica
authors.initials: J
authors.lastname: Rowley
authors.forename: Keith
authors.initials: K
authors.lastname: Dredge
authors.forename: Cai Ping
authors.initials: CP
authors.lastname: Li
authors.forename: Edward
authors.initials: E
authors.lastname: Hammond
authors.forename: Kat
authors.initials: K
authors.lastname: Davis
authors.forename: Laura
authors.initials: L
authors.lastname: Sarimaa
authors.forename: Job
authors.initials: J
authors.lastname: Harenberg
authors.forename: Ian
authors.initials: I
authors.lastname: Bytheway
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005966:Glucuronidase / Q000037:antagonists & inhibitors*; D006497:Heparan Sulfate / Q000031:analogs & derivatives*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D012503:Saponins / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099175:Heparanase
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D005966:Glucuronidase; D006497:Heparan Sulfate; D012503:Saponins; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase; C557899:PG 545