Article

Thalidomide is an inhibitor of angiogenesis.

Department of Surgery, Children's Hospital, Harvard Medical School, Boston 02115.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 05/1994; 91(9):4082-5. DOI: 10.1097/00006982-199616030-00022
Source: PubMed

ABSTRACT Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.

1 Bookmark
 · 
138 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Drug repositioning or repurposing has received much coverage in the scientific literature in recent years and has been responsible for the generation of both new intellectual property and investigational new drug submissions. The literature indicates a significant trend toward the use of computational- or informatics-based methods for generating initial repositioning hypotheses, followed by focused assessment of biological activity in phenotypic assays. Another viable method for drug repositioning is in vitro screening of known drugs or drug-like molecules, initially in disease-relevant phenotypic assays, to identify and validate candidates for repositioning. This approach can use large compound libraries or can focus on subsets of known drugs or drug-like molecules. In this short review, we focus on ways to generate and validate repositioning candidates in disease-related in vitro and phenotypic assays, and we discuss specific examples of this approach as applied to a variety of disease areas. We propose that in vitro screens offer several advantages over biochemical or in vivo methods as a starting point for drug repositioning. © 2014 Society for Laboratory Automation and Screening.
    Journal of Biomolecular Screening 12/2014; · 2.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a severe, progressive fibrotic disease of the lung of unknown etiology that affects approximately 150,000 patients in the United States. It carries a median survival of two to three years, but clinical course can vary markedly from patient to patient. There has been no established treatment for IPF, but recent advances in coordinated clinical trials through groups such as IPFnet and academia–industry partnerships have allowed this relatively rare disease to be studied in much greater depth. Historically, the default therapy for IPF was a combination of prednisone, N-acetylcysteine, and azathioprine, but recent trials have shown that this regimen actually increases mortality. An enormous body of work in recent years, spanning the bench to the bedside, has radically altered our understanding of the molecular mechanisms underlying IPF. Newer modalities, particularly those involving monoclonal antibodies targeted at specific pathways known to contribute to the fibrotic process, have generated a great deal of excitement in the field, and recent clinical trials on therapies such as pirfenidone and nintedanib herald a new era in targeted IPF therapies.
    Annals of Medicine. 01/2015;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite having caused one of the greatest medical catastrophies of the last century through its teratogenic side-effects, thalidomide continues to be an important agent in the treatment of leprosy and cancer. The protein cereblon, which forms an E3 ubiquitin ligase compex together with damaged DNA-binding protein 1 (DDB1) and cullin 4A, has been recently indentified as a primary target of thalidomide and its C-terminal part as responsible for binding thalidomide within a domain carrying several invariant cysteine and tryptophan residues. This domain, which we name CULT (cereblon domain of unknown activity, binding cellular ligands and thalidomide), is also found in a family of secreted proteins from animals and in a family of bacterial proteins occurring primarily in δ-proteobacteria. Its nearest relatives are yippee, a highly conserved eukaryotic protein of unknown function, and Mis18, a protein involved in the priming of centromeres for recruitment of CENP-A. Searches for distant homologs point to an evolutionary relationship of CULT, yippee, and Mis18 to proteins sharing a common fold, which consists of two four-stranded β-meanders packing at a roughly right angle and coordinating a zinc ion at their apex. A β-hairpin inserted into the first β-meander extends across the bottom of the structure towards the C-terminal edge of the second β-meander, with which it forms a cradle-shaped binding site that is topologically conserved in all members of this fold. We name this the β-tent fold for the striking arrangement of its constituent β-sheets. The fold has internal pseudosymmetry, raising the possibility that it arose by duplication of a subdomain-sized fragment.
    PLoS Computational Biology 01/2015; 11(1):e1004023. · 4.83 Impact Factor

Full-text (2 Sources)

Download
56 Downloads
Available from
May 21, 2014