Proline isosteres in a series of 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitors of IGF-1R kinase and IR kinase

Sampognaro, Anthony J.; Wittman, Mark D.; Carboni, Joan M.; Chang, Chiehying; Greer, Ann; Hurlburt, Warren; Sack, John S.; Vyas, Dolatrai M.

doi:10.1016/j.bmcl.2010.07.045

Cited by 20 publications

(15 citation statements)

References 13 publications

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“…37 In the reactant state systems, the AMP–PCP (ATP analogue) was replaced with ATP. The substrate peptide found in the X-ray structure was included without modification.…”

Section: Methodsmentioning

confidence: 99%

Dynamic, structural and thermodynamic basis of insulin-like growth factor 1 kinase allostery mediated by activation loop phosphorylation

Nam

2017

Chem. Sci.

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“…37 In the reactant state systems, the AMP–PCP (ATP analogue) was replaced with ATP. The substrate peptide found in the X-ray structure was included without modification.…”

Section: Methodsmentioning

confidence: 99%

Dynamic, structural and thermodynamic basis of insulin-like growth factor 1 kinase allostery mediated by activation loop phosphorylation

Nam

2017

Chem. Sci.

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“…The subsequent structural optimizations were carried out to give proline isosteres with slight decreases in activities [41]. Among them, the acyclic analog 21 showed experimentally equipotent to other cyclic proline isosteres, demonstrating that a cyclic proline linker was not necessary for kinase potency.…”

Section: Pyrrolotriazinementioning

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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“…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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Proline isosteres in a series of 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitors of IGF-1R kinase and IR kinase

Cited by 20 publications

References 13 publications

Dynamic, structural and thermodynamic basis of insulin-like growth factor 1 kinase allostery mediated by activation loop phosphorylation

Dynamic, structural and thermodynamic basis of insulin-like growth factor 1 kinase allostery mediated by activation loop phosphorylation

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

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