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

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.

Nanoparticle delivery of a peptide targeting EGFR signaling

“…Protein interactions crucially mediate many signaling pathways controlling cellular proliferation and apoptosis; blocking such interactions in an intracellular compartment holds great therapeutic potential for the development of anti-cancer drugs [1, 2]. Small molecules, however, have difficulty targeting these interactions because of the nature of the protein interface, which is normally extensive, shallow and hydrophobic [3]. Moreover, antibody therapeutics, albeit popular candidates because of advantages including high affinity and specificity, also demonstrate serious disadvantages, such as unfavorable immunogenicity, low drug penetration and hypersensitivity reactions [4].…”

At the edge of translation – materials to program cells for directed differentiation

“…The precise cellular mechanisms underlying the effects of adhesion ligand presentation are being intensely investigated and are speculated to result, at least in part, from modulation of adhesion contacts and clustering of cellular receptor that in turn modulate the cytoskeleton and intrinsic cell signaling pathways (Chen et al , 1997; Geiger et al , 2001; Comisar et al , 2006; Discher et al , 2009). Interestingly, as there is better understanding of the biological basis of these material’s biophysical interactions at the nanoscale, the material composition itself can be designed to serve as an extrinsic cue to trigger specific signal transduction pathways, as demonstrated by direct induction of focal adhesion kinase signaling in a recent report (Poondra et al , 2009). In vivo , mechanically tailored material systems, both natural and synthetic, have demonstrated efficacy in aiding regeneration of cardiac muscle (van Amerongen et al , 2006; Valarmathi et al , 2010) and PDL (Moioli et al , 2008), as well as modulating scar tissue formation (Agrawal et al , 2010).…”

Peptide-Based Nanostructures for Cancer Diagnosis and Therapy

“…Small molecules usually have difficulties in precisely targeting protein interactions for the reasons that protein interfaces are normally extensive, shallow, and hydrophobic in nature [80]. Therapeutics based on antibodies which show high affinities and specificities to tumors still have disadvantages such as unfavorable immunogenicity, low drug penetration, and undesired hypersensitivity reactions [81].…”