Discovery and SAR of Thiazolidine-2,4-dione Analogues as Insulin-like Growth Factor-1 Receptor (IGF-1R) Inhibitors via Hierarchical Virtual Screening

Liu, Xiaofeng; Xie, Hua; Luo, Cheng; Tong, Linjiang; Wang, Yi; Peng, Ting; Ding, Jian; Jiang, Hualiang; Li, Honglin

doi:10.1021/jm901798e

Cited by 35 publications

(27 citation statements)

References 15 publications

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“…In our group, Liu et al discovered a series of novel IGF-1R inhibitors using a hierarchical virtual screening approach, all of which had the scaffold of thiazolidine-2,4-dione (TDZ) usually emerging in antidiabetic agents targeting nuclear receptor and peroxisome proliferators-activated receptor-(PPAR ) or inhibitors against phosphoinositide 3-kinase (PI3K ) [29]. The representative compound 8 exhibited IGF-1R inhibition in vitro with IC 50 value of 1.71 μM, and then further optimization was executed to get more potent IGF-1R inhibitors.…”

Section: Thiazolidinedionesmentioning

confidence: 99%

Insulin-like Growth Factor-1 Receptor (IGF-1R) Kinase Inhibitors in Cancer Therapy: Advances and Perspectives

Xue¹,

Cao²,

Zhong³

et al. 2012

CPD

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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.

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Section: Thiazolidinedionesmentioning

confidence: 99%

Insulin-like Growth Factor-1 Receptor (IGF-1R) Kinase Inhibitors in Cancer Therapy: Advances and Perspectives

Xue¹,

Cao²,

Zhong³

et al. 2012

CPD

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“…Increased proteasomal degradation by glitazones is not limited to cyclin D1, but includes important apoptosis regulatory proteins such as FLICE-inhibitory protein (FLIP) and beta-catenin, and the transcription factor Sp1 (Yang et al, 2008; Wei et al, 2009). Additional targets of glitazone-based drug design potentially exploitable for cancer therapy are: SHP-2, a tyrosine phosphatase that mediates cell signaling by growth factors and cytokines via the mitogen-activated protein kinase (MAPK) pathway (Geronikaki et al, 2008); Pim-1 and Pim-2 protein kinases frequently overexpressed in prostate cancer and certain forms of leukemia and lymphoma (Xia et al, 2009); Insulin-like growth factor-1 receptor, which may affect cell proliferation and survival (Liu et al, 2010). …”

Section: Pparγ-unrelated Effects Of Glitazones and Drug Discoverymentioning

confidence: 99%

Pleiotropic Effects of Glitazones: A Double Edge Sword?

Salomone¹

2011

Front. Pharmacol.

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Glitazones (thiazolidinediones) are drugs used for diabetes mellitus type 2. By binding to peroxisome proliferator-activated receptor γ (PPARγ) they modulate transcription of genes of carbohydrate and lipid metabolism. Through PPARγ stimulation, however, glitazones also affect other genes, encompassing inflammation, cell growth and differentiation, angiogenesis, which broads their therapeutic potential. The gene expression profile induced by each glitazone shows peculiarities, which may affect its benefit/risk balance; indeed, troglitazone and rosiglitazone have been associated with liver failure and coronary disease, respectively; whether or not these severe adverse effects are solely related to PPARγ remains yet unclear, since glitazones exert also PPARγ-independent effects. Glitazone chemistry serves as scaffold for synthesizing new compounds with PPARγ-independent pharmacological properties and we report here a preliminary observation of inhibition of vasoconstriction by troglitazone in isolated vessels, an effect that appears fast, reversible, and PPARγ-independent. Pleiotropic effects of glitazones need specific attention in terms of drug safety, but also provide basis for drug development and novel experimental therapeutics.

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“…Liu et al discovered two potent IGF-1R kinase inhibitors via hierarchical strategy based virtual screening (pharmacophore screening and docking), which efficiently reduced the number of “nonhits” passed to docking stage and consequently reduced the computational cost [36]. …”

Section: Methodsmentioning

confidence: 99%

iDrug: a web-accessible and interactive drug discovery and design platform

et al. 2014

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BackgroundThe progress in computer-aided drug design (CADD) approaches over the past decades accelerated the early-stage pharmaceutical research. Many powerful standalone tools for CADD have been developed in academia. As programs are developed by various research groups, a consistent user-friendly online graphical working environment, combining computational techniques such as pharmacophore mapping, similarity calculation, scoring, and target identification is needed.ResultsWe presented a versatile, user-friendly, and efficient online tool for computer-aided drug design based on pharmacophore and 3D molecular similarity searching. The web interface enables binding sites detection, virtual screening hits identification, and drug targets prediction in an interactive manner through a seamless interface to all adapted packages (e.g., Cavity, PocketV.2, PharmMapper, SHAFTS). Several commercially available compound databases for hit identification and a well-annotated pharmacophore database for drug targets prediction were integrated in iDrug as well. The web interface provides tools for real-time molecular building/editing, converting, displaying, and analyzing. All the customized configurations of the functional modules can be accessed through featured session files provided, which can be saved to the local disk and uploaded to resume or update the history work.ConclusionsiDrug is easy to use, and provides a novel, fast and reliable tool for conducting drug design experiments. By using iDrug, various molecular design processing tasks can be submitted and visualized simply in one browser without installing locally any standalone modeling softwares. iDrug is accessible free of charge at http://lilab.ecust.edu.cn/idrug.

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Discovery and SAR of Thiazolidine-2,4-dione Analogues as Insulin-like Growth Factor-1 Receptor (IGF-1R) Inhibitors via Hierarchical Virtual Screening

Cited by 35 publications

References 15 publications

Insulin-like Growth Factor-1 Receptor (IGF-1R) Kinase Inhibitors in Cancer Therapy: Advances and Perspectives

Insulin-like Growth Factor-1 Receptor (IGF-1R) Kinase Inhibitors in Cancer Therapy: Advances and Perspectives

Pleiotropic Effects of Glitazones: A Double Edge Sword?

iDrug: a web-accessible and interactive drug discovery and design platform

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