“… A scatter plot of the buried surface area (Å 2 ) of each crystal lattice pair of IR or IGF1R kinase domains. A dashed line (red) at 800 Å 2 represents the minimal threshold of a biological interface ( Bahadur et al, 2004 ) and a list of structures used in analysis and the numbering of the corresponding kinase pairs generated for each ( Hubbard et al, 1994 ; Hubbard, 1997 ; Favelyukis et al, 2001 ; Parang et al, 2001 ; Pautsch et al, 2001 ; Till et al, 2001 ; Munshi et al, 2002 ; Hu et al, 2003 ; Li et al, 2003 ; Munshi et al, 2003 ; Depetris et al, 2005 ; Li et al, 2005 ; Velaparthi et al, 2007 ; Mayer et al, 2008 ; Wu et al, 2008 ; Miller et al, 2009 ; Patnaik et al, 2009 ). DOI: http://dx.doi.org/10.7554/eLife.03772.030 10.7554/eLife.03772.031 Figure 8—figure supplement 2.…”
The type I insulin-like growth factor receptor (IGF1R) is involved in growth and survival of normal and neoplastic cells. A ligand-dependent conformational change is thought to regulate IGF1R activity, but the nature of this change is unclear. We point out an underappreciated dimer in the crystal structure of the related Insulin Receptor (IR) with Insulin bound that allows direct comparison with unliganded IR and suggests a mechanism by which ligand regulates IR/IGF1R activity. We test this mechanism in a series of biochemical and biophysical assays and find the IGF1R ectodomain maintains an autoinhibited state in which the TMs are held apart. Ligand binding releases this constraint, allowing TM association and unleashing an intrinsic propensity of the intracellular regions to autophosphorylate. Enzymatic studies of full-length and kinase-containing fragments show phosphorylated IGF1R is fully active independent of ligand and the extracellular-TM regions. The key step triggered by ligand binding is thus autophosphorylation.DOI:
http://dx.doi.org/10.7554/eLife.03772.001
“… A scatter plot of the buried surface area (Å 2 ) of each crystal lattice pair of IR or IGF1R kinase domains. A dashed line (red) at 800 Å 2 represents the minimal threshold of a biological interface ( Bahadur et al, 2004 ) and a list of structures used in analysis and the numbering of the corresponding kinase pairs generated for each ( Hubbard et al, 1994 ; Hubbard, 1997 ; Favelyukis et al, 2001 ; Parang et al, 2001 ; Pautsch et al, 2001 ; Till et al, 2001 ; Munshi et al, 2002 ; Hu et al, 2003 ; Li et al, 2003 ; Munshi et al, 2003 ; Depetris et al, 2005 ; Li et al, 2005 ; Velaparthi et al, 2007 ; Mayer et al, 2008 ; Wu et al, 2008 ; Miller et al, 2009 ; Patnaik et al, 2009 ). DOI: http://dx.doi.org/10.7554/eLife.03772.030 10.7554/eLife.03772.031 Figure 8—figure supplement 2.…”
The type I insulin-like growth factor receptor (IGF1R) is involved in growth and survival of normal and neoplastic cells. A ligand-dependent conformational change is thought to regulate IGF1R activity, but the nature of this change is unclear. We point out an underappreciated dimer in the crystal structure of the related Insulin Receptor (IR) with Insulin bound that allows direct comparison with unliganded IR and suggests a mechanism by which ligand regulates IR/IGF1R activity. We test this mechanism in a series of biochemical and biophysical assays and find the IGF1R ectodomain maintains an autoinhibited state in which the TMs are held apart. Ligand binding releases this constraint, allowing TM association and unleashing an intrinsic propensity of the intracellular regions to autophosphorylate. Enzymatic studies of full-length and kinase-containing fragments show phosphorylated IGF1R is fully active independent of ligand and the extracellular-TM regions. The key step triggered by ligand binding is thus autophosphorylation.DOI:
http://dx.doi.org/10.7554/eLife.03772.001
“…A series of 3, 5-disubstituted-1H-pyrrolo[2,3-b]pyridines was identified for IGF-1R inhibitors with IC 50 values fluctuating from a micromolar level to a single digit nanomolar level [32]. Whilst they exhibited certain selectivity versus a panel of 36 other kinases, showing moderate cellular potency in NIH-3T3 cell line, but they were essentially equipotent against IR in both enzymatic and cellular assays.…”
The insulin-like growth factors (IGF) and their receptors play pivotal roles in cellular signaling transduction and thus regulate cell growth, differentiation, apoptosis, transformation and other important physiological progresses. The insulin-like growth factor 1 receptor (IGF-1R) mainly engages in the Ras/mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, and also forms cross-talk with the epidermal growth factor receptor (EGFR) pathway. Currently, it draws more attention since its overexpression has been demonstrated in various human cancers, such as colorectal cancer, breast cancer, prostate cancer and lung tumors, thus the strategy targeting the IGF-1R would be promising in treatment of these cancers. There are already dozens of agents developed for the inhibition of IGF-1R, which are categorized into monoclonal antibodies, small molecule inhibitors and so on. While in this review, small molecule inhibitors would be the focus for detailed discussion. Herein, we updated previously reported research papers and reviews in this field and summarized developments of small molecule inhibitors up to 2011. Finally, we proposed the application of network pharmacology methods to reconsider the clinical use of inhibitors with concomitant IR inhibition or other kinases inhibition, hoping that more optimal combinations would be obtained for cancer therapy.
“…The tosylated 7‐azaindole MMV024114 ( 542 ) is another unreported compound, but this scaffold has appeared as an N‐protected intermediate in the synthesis of numerous 3,5‐diaryl kinase inhibitors. However, structural data of these compounds suggest that both free nitrogen atoms are important for potent kinase inhibitory activity …”
The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.
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