Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinase inhibitors towards JNK selectivity

Chamberlain, Stanley D.; Redman, Anikó M.; Wilson, Joseph W.; Deanda, Felix; Shotwell, J. Brad; Gerding, Roseanne M.; Lei, Huangshu; Yang, Bin; Stevens, Kirk L.; Hassell, Anne M.; Shewchuk, Lisa M.; Leesnitzer, M. Anthony; Smith, Jeffery L.; Sabbatini, Peter; Atkins, Charity; Groy, Arthur; Rowand, Jason L.; Kumar, Rakesh; Mook, Robert A.; Moorthy, Ganesh S.; Patnaik, Samarjit

doi:10.1016/j.bmcl.2008.11.077

Cited by 51 publications

(44 citation statements)

References 10 publications

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“…As a consequence, structural optimizations would be focused on analogs which would be more stable toward in vivo hydrolysis in the stomach and especially in pharmaceutical formulations with pH<4. Besides, since 19 also exhibited equipotent activity against JNKs, the researchers developed a series of analogs according to their preference, which showed nearly 500-fold selectivity of IGF-1R over JNK1 [38].…”

Section: Pyrrolopyrimidinementioning

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: Pyrrolopyrimidinementioning

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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“…Based on the structural information and binding analysis done by other authors for several JNK variants (35)(36)(37)(38)(39)(40)(41)(42), we expected Langmuirian kinetics with 1:1 stoichiometry for the studied interactions. Some of the factors that can cause deviations from pseudo-first order approximation of binding data include: mass transfer effects, immobilized ligand density, inhomogeneity of immobilized ligand or soluble analyte, immobilization chemistry, and rebinding of dissociated analyte (43).…”

Section: -10mentioning

confidence: 68%

Enzyme Kinetics and Interaction Studies for Human JNK1β1 and Substrates Activating Transcription Factor 2 (ATF2) and c-Jun N-terminal kinase (c-Jun)

Figuera-Losada

LoGrasso

2012

Journal of Biological Chemistry

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Background: JNK1␤1 has a role in diabetes and unique substrate interactions could affect function. Results: JNK1␤1 showed lower affinity and capacity to phosphorylate ATF2 than other variants. ATP binding and JNK1␤1 activation affected substrate interaction rates and affinities. Conclusion: JNK1␤1 activation and ATP binding affects interactions with substrates. Significance: First kinetic and biochemical characterization of a ␤ JNK splice variant.

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“…3,[21][22][23][24] Overall structure of JNK1 and the superimposed model of five JNK1 inhibitors are represented in Figure 1. JNK1 inhibitors formed commonly two hydrogen bonds with backbone amide proton of M111 and backbone carbonyl oxygen of E109, respectively.…”

Section: Resultsmentioning

confidence: 99%

Docking Study of Flavonols and Human c-Jun N-terminal Kinase 1

Lee¹,

Jeong²,

Heo³

et al. 2010

Bulletin of the Korean Chemical Society

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c-Jun N-terminal kinase 1 (JNK1) is involved in apoptosis, cell differentiation and proliferation. It has been reported that a flavonol, quercetin, induces cell apoptosis and JNK inhibition. In order to understand the interactions of quercetin and JNK1, we performed receptor-oriented pharmacophore based in silico screening and determined a binding model of human JNK1 and quercetin at the ATP binding site of JNK1. 5-OH of A-ring and carbonyl oxygen of C-ring of quercetin participated in hydrogen bonding interactions with backbone of E109 and M111. Additionally, 3'-OH of quercetin formed a hydrogen bond with backbone of I32. One hydrophobic interaction is related on the binding of quercetin to JNK1 with I32, N114, and V158. Based on this model, we conducted a docking study with other 8 flavonols to find possible flavonoids inhibitors of JNK1. We proposed that one flavonols, rhamnetin, can be a potent inhibitor of JNK and 5-OH of A-ring and 3'-OH of B-ring of flavonols are the essential features for JNK1 inhibition.

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Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinase inhibitors towards JNK selectivity

Cited by 51 publications

References 10 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

Enzyme Kinetics and Interaction Studies for Human JNK1β1 and Substrates Activating Transcription Factor 2 (ATF2) and c-Jun N-terminal kinase (c-Jun)

Docking Study of Flavonols and Human c-Jun N-terminal Kinase 1

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