title: Thrombospondin-1 mimetic peptide inhibitors of angiogenesis and tumor growth: design, synthesis, and optimization of pharmacokinetics and biological activities.
abstract: The heptapeptide 1, NAc-Gly-Val-DIle-Thr-Arg-Ile-ArgNHEt, a structurally modified fragment derived from the second type-1 repeat of thrombospondin-1 (TSP-1), is known to possess antiangiogenic activity. However, therapeutic utility could not be demonstrated because this peptide has a very short half-life in rodents. To optimize the PD/PK profile of 1, we initiated a systematic SAR study. The initial structural modifications were performed at positions 5 and 7 of peptide 1 and at the N- and C-termini. Out of several hundred peptides synthesized, the nonapeptide 5 (ABT-526) emerged as a promising lead. ABT-526 inhibited VEGF-induced HMVEC cell migration and tube formation in the nanomolar range and increased apoptosis of HUAEC cells. ABT-526 showed acceptable PK in rodents, dog, and monkey. ABT-526, when incorporated in an angiogenic pellet implanted in the rat cornea at 10 microM, reduced neovascularization by 92%. Substitution of DalloIle in place of DIle in ABT-526 provided nonapeptide 6 (ABT-510), which was 30-fold less active than ABT-526 in the EC migration but 20-fold more active in the tube formation assay. In comparison to ABT-526, ABT-510 has increased water solubility and slower clearance in dog and monkey. Radiolabeled ABT-510 demonstrated saturable binding to HMVEC cells at 0.02-20 nM concentrations and was displaceable by TSP-1. ABT-510 and ABT-526 were shown to significantly increase apoptosis of HUAEC cells. ABT-510 was effective in blocking neovascularization in the mouse Matrigel plug model and inhibited tumor growth in the mouse Lewis lung carcinoma model. Previous studies had shown that ABT-510 was effective in inhibiting the outgrowth of murine melanoma metastases in syngeneic mice and in blocking the growth of human bladder carcinoma implanted in nude mice. It had been also shown that ABT-510 could regress tumor lesions in pet dogs or cause unexpected stabilization of the disease in advanced canine cancer. ABT-526 and ABT-510 are the first compounds in the class of potent inhibitors of angiogenesis that mimic the antiangiogenic function of TSP-1. ABT-510 is currently in phase II clinical studies.
authors.affiliation: Global Pharmaceutical Research and Development Organization of Abbott Laboratories, Abbott Laboratories, Abbott Park, Illinois 60064, USA. fortuna.haviv@abbott.com
authors.forename: Fortuna
authors.initials: F
authors.lastname: Haviv
authors.forename: Michael F
authors.initials: MF
authors.lastname: Bradley
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Kalvin
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schneider
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Davidson
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Majest
authors.forename: Laura M
authors.initials: LM
authors.lastname: McKay
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Haskell
authors.forename: Randy L
authors.initials: RL
authors.lastname: Bell
authors.forename: Bach
authors.initials: B
authors.lastname: Nguyen
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Surber
authors.forename: John T
authors.initials: JT
authors.lastname: Uchic
authors.forename: James
authors.initials: J
authors.lastname: Ferrero
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Leal
authors.forename: Rae D
authors.initials: RD
authors.lastname: Record
authors.forename: Jason
authors.initials: J
authors.lastname: Hodde
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Badylak
authors.forename: Richard R
authors.initials: RR
authors.lastname: Lesniewski
authors.forename: Jack
authors.initials: J
authors.lastname: Henkin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002196:Capillaries / Q000166:cytology; D002633:Chemotaxis / Q000187:drug effects; D003315:Cornea / Q000098:blood supply / Q000187:drug effects; D004285:Dogs; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D019700:Thrombospondin 1 / Q000737:chemistry*; D014470:Umbilical Cord / Q000166:cytology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C500617:NAc-Sar-Gly-Val-(d-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt; D009842:Oligopeptides; D019700:Thrombospondin 1