Discovery of Indoline-Based, Natural-Product-like Compounds as Probes of Focal Adhesion Kinase Signaling Pathways

Steacie Institute for Molecular Sciences, National Research Council of Canada, 100 Sussex Drive, Ottawa, Ontario, Canada.
Journal of Combinatorial Chemistry (Impact Factor: 4.93). 02/2009; 11(2):303-9. DOI: 10.1021/cc8001525
Source: PubMed

ABSTRACT With the goal of identifying small molecule modulators of protein-protein interactions, we developed a solid-phase synthesis method, which was then successfully utilized in a library generation of 164 aminoindoline-derived, natural-product-like compounds. This library and several other related intermediates synthesized during this project were then subjected to different biological assays in search of small molecule modulators of focal adhesion kinase (FAK)-mediated signaling pathways. This study included (i) an in vitro, full length FAK inhibition assay, (ii) a cell proliferation assay, and (iii) a wound healing assay. In FAK inhibition assay, eight library members (5-12) and three aminoindoline derivatives (13, 14, and 2) were identified as promising candidates. Compounds 13 and 2 inhibited the FAK activity by 25-45% at 10 microM. These two lead compounds also showed activity in a wound healing assay. To our knowledge, these aminoindoline-derived small molecules belong to a new family of FAK inhibitors.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A modular approach to explore the macro-moiety and subsequent "stitching technol-cyclic chemical space around an amino-ogy". Through screening of a zebrafish as-Keywords: Medicinal chemistry / Angiogen-indoline scaffold is developed. This is say, several antiangiogenesis agents are esis / Chemical probes / Molecular diver-achieved by incorporating an amino acid identified. sity / Nitrogen heterocycles / Macrocycles 0000, 0–0 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: An elegant reagent-controlled strategy has been developed for the generation of a diverse range of biologically active scaffolds from a chiral bicyclic lactam. Reduction of the chiral lactam with LAH or alkylation with LHMDS to trigger different cyclization reactions have been shown to generate privileged scaffolds, such as pyrrolidines, indolines, and cyclotryptamines. Their amenability to substitution allows us to create various compound libraries by using these scaffolds. In silico studies were used to estimate the drug-like properties of these compounds. Selected compounds were subjected to anticancer screening by using three different cell lines. In addition, all these compounds were subjected to antibacterial screening to gauge the spectrum of biological activity that was conferred by our DOS methodology. Gratifyingly, with no additional iterative cycles, our method directly generated anticancer compounds with potency at low nanomolar concentrations, as represented by spiroindoline 14.
    Chemistry - An Asian Journal 07/2014; DOI:10.1002/asia.201201203 · 3.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: EGFR serves as an important therapeutic target because of its over-expression in many cancers. In this study, we investigated a peptide-based therapy aimed at blocking intracellular protein-protein interactions during EGFR signaling and evaluated a targetable lipid carrier system that can deliver peptides to intracellular targets in human cancer cells. EEEEpYFELV (EV), a nonapeptide mimicking the Y845 site of EGFR which is responsible for STAT5b phosphorylation, was designed to block EGFR downstream signaling. EV was loaded onto LPH nanoparticles that are comprised of a membrane/core structure including a surface-grafted polyethylene glycol (PEG) used to evade the reticuloendothelial system (RES) and anisamide (AA) for targeting the sigma receptor over-expressed in H460 human lung cancer cells. EV formulated with PEGylated and targeted LPH (LPH-PEG-AA) was taken up by the tumor cells and trafficked to the cytoplasm with high efficiency. Using this approach, EV acted as a dominant negative inhibitor of STAT5b phosphorylation, arrested cell proliferation, and induced massive apoptosis. Intravenous administration of EV loaded in LPH-PEG-AA led to efficient EV peptide delivery to the tumor in a xenograft mouse model, and multiple injections inhibited tumor growth in a dose-dependent manner. Our findings offer proof-of-concept for an intracellular peptide-mediated cancer therapy that is delivered by carefully designed nanoparticles.
    Journal of Controlled Release 08/2011; 157(2):279-86. DOI:10.1016/j.jconrel.2011.08.014 · 7.26 Impact Factor

Full-text (2 Sources)

Available from
Jul 18, 2014