Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment

Mayer, Scott C.; Banker, A.; Boschelli, Frank; Di, Li; Johnson, Mark R.; Kenny, Cynthia Hess; Krishnamurthy, Girija; Kutterer, Kristina M. K.; Moy, Fred; Petusky, Susan; Ravi, Malini; Tkach, Diane; Tsou, Hwei‐Ru; Xu, Weixin

doi:10.1016/j.bmcl.2008.04.044

Cited by 57 publications

(33 citation statements)

References 21 publications

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“…Wyeth Research (now part of Pfizer) has disclosed isoquinolinedione series as a viable lead for IGF-1R inhibitors from a highthroughput screening, providing a unique scaffold [63]. The representative compound 39 bound to IGF-1R with a binding constant K D value of 614 nM (and IC 50 = 2.42 M), and the co-crystal study of 39 provided a typical binding manner in the ATP binding pocket of the IGF-1R, in which the compound formed a hydrogen bonding network with residues Glu 1080 and Met 1082.…”

Section: Isoquinolinedione and Cyanoquinolinesmentioning

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: Isoquinolinedione and Cyanoquinolinesmentioning

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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“…To do this, we examined crystal structures of the IGF-1R kinase that, although C-terminally truncated after amino acid 1256, encompass the SFYYS motif. These include crystal structures with the kinase A-loop in various states of phosphorylation (from unphosphorylated to fully phosphorylated) and variously complexed with ATP mimetics, inhibitors, and phospho-acceptor peptide substrates (7,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). In these structures, the unphosphorylated SFYYS motif universally adopts a conformation tightly packed against helices ␣I and ␣E of the kinase C-lobe (Fig.…”

Section: Model For Function Of Ser-1248 In Phosphorylated and Unphospmentioning

confidence: 99%

“…We also used the available crystal structures that, although truncated below amino acid 1256, encompass the SFYYS motif (7,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) and enabled us to explore the structural basis for this motif in regulating IGF-1R activity. Our findings indicate that a direct regulatory interaction of the C terminus with the kinase domain can be controlled by phosphorylation of Ser-1248.…”

Section: The Igf-1rmentioning

confidence: 99%

Serine Phosphorylation of the Insulin-like Growth Factor I (IGF-1) Receptor C-terminal Tail Restrains Kinase Activity and Cell Growth

Kelly

Buckley

Kiely

et al. 2012

Journal of Biological Chemistry

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“…IGF-1R has been widely targeted to decrease cellular proliferation and promote apoptosis in cancers [4,5]. Crystallographic structures of IGF-1R cocrystallized with various ligands have been identified [3,[6][7][8]. The biological activity of these ligands depends on the interactions with certain residues in the ATP binding sites of IGF-1R kinase domain, which serve as hydrogen bond donors, acceptors, or hydrophobic pockets.…”

Section: Introductionmentioning

confidence: 99%

Application of Group-Based QSAR and Molecular Docking in the Design of Insulin-Like Growth Factor Antagonists

Abdullahi¹,

Abdualkader²,

Abdulsamat³

et al. 2015

Trop. J. Pharm Res

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Purpose: To identify the structural requirements for designing a lead key for insulin-like growth factor (IGF-1R) inhibition using group-based quantitative structure activity relationship (GQSAR Met 1126, Arg, 1128, Met 1052, GLU 1050, Met 1112, Leu 1051, Met 1049, Val 1033 at ATP binding sites of IGF-1R kinase domain. Conclusion:The generated models provide a site-specific insight into the structural requirements for IGF-1R inhibition which can be used to design and develop potent inhibitors.

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Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment

Cited by 57 publications

References 21 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

Serine Phosphorylation of the Insulin-like Growth Factor I (IGF-1) Receptor C-terminal Tail Restrains Kinase Activity and Cell Growth

Application of Group-Based QSAR and Molecular Docking in the Design of Insulin-Like Growth Factor Antagonists

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