A Highly Selective Dual Insulin Receptor (IR)/Insulin-like Growth Factor 1 Receptor (IGF-1R) Inhibitor Derived from an Extracellular Signal-regulated Kinase (ERK) Inhibitor

Anastassiadis, Theonie; Duong‐Ly, Krisna C.; Deacon, Sean; Lafontant, Alec; Ma, Haiching; Devarajan, Karthik; Dunbrack, Roland L.; Wu, Jiangxue; Peterson, Jeffrey R.

doi:10.1074/jbc.m113.505032

Cited by 14 publications

(19 citation statements)

References 42 publications

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“…An additional limitation is that the differences in mean receptor mRNA expression across patient groups in this study are relatively small. Despite these limitations, the potential significance of our observations is highlighted by the growing interest in the role of the insulin/IGF pathway in cancer and IR/IGF1R inhibitors as potential therapies (22, 24, 26). To date, IR and IR isoforms have been understudied in the gastrointestinal tract, and our work suggests that further studies focusing on these receptors and relative IR-A and IR-B expression are needed to better understand their roles in initiation and pathophysiology of colorectal pre-cancerous lesions.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a number of studies have shown that IGF1R confers resistance to radiation therapy and chemotherapy (17, 18), and clinical evidence links IGF1R over-expression to colorectal tumor formation and progression (19, 20). Although IGF1R inhibitors showed a potential to reduce tumor growth (21, 22), recent reports suggested that IR may permit tumors to resist IGF1R inhibition, which led to the development of dual IGF1R/IR inhibitors (23–26). …”

Section: Introductionmentioning

confidence: 99%

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Reduced Insulin-like Growth Factor I Receptor and Altered Insulin Receptor Isoform mRNAs in Normal Mucosa Predict Colorectal Adenoma Risk

Santoro

Andres

Galanko

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Hyperinsulinemia resulting from obesity and insulin resistance is associated with increased risk of many cancers, but the biology underlying this risk is unclear. We hypothesized that increased mRNA levels of the insulin-like growth factor 1 receptor (IGF1R) versus the insulin receptor (IR) or elevated ratio of IR-A:IR-B isoforms in normal rectal mucosa would predictadenoma risk, particularly in individuals with high body mass index (BMI) or plasma insulin. Methods Biopsies from normal rectal mucosa were obtained from consenting patients undergoing routine colonoscopy at UNC Hospitals. Subjects with colorectal adenomas were classified as cases (n = 100) and were matched to adenoma-free controls (n = 98) based on age, sex and BMI. IGF1R and IR mRNA levels were assessed by qRT-PCR, and IR-A:IR-B mRNA ratios by standard PCR. Plasma insulin and crypt apoptosis were measured by ELISA and TUNEL, respectively. Logistic regression models examined relationships between receptor mRNAs, BMI, plasma insulin and adenoma risk. Results Unexpectedly, cases were significantly more likely to have lower IGF1R mRNA levels than controls. No overall differences in total IR mRNA or IR-A:IR-B ratios were observed between cases and controls. Interestingly, in patients with high plasma insulin, increased IR-A:IR-B ratio was associated with increased likelihood of having adenomas. Conclusions Our work shows novel findings that reduced IGF1R mRNA and, during high plasma insulin, increased IR-A:IR-B ratios in normal rectal mucosa are associated with colorectal adenoma risk. Impact Our work provides evidence supporting a link between IGF1R and IR isoform expression levels and colorectal adenoma risk.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reduced Insulin-like Growth Factor I Receptor and Altered Insulin Receptor Isoform mRNAs in Normal Mucosa Predict Colorectal Adenoma Risk

Santoro

Andres

Galanko

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…In addition to this set, five additional compounds were profiled: Aurora Kinase Inhibitor II (CAS no. 331770-21-9, purchased from EMD Biosciences); irfin1 (Anastassiadis et al, 2013) (CAS no. 1177970-73-8, purchased from EMD Biosciences); and afatinib (CAS no.…”

Section: Methodsmentioning

confidence: 99%

Kinase Inhibitor Profiling Reveals Unexpected Opportunities to Inhibit Disease-Associated Mutant Kinases

et al. 2016

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Summary Small-molecule kinase inhibitors have typically been designed to inhibit wild-type kinases rather than the mutant forms that frequently arise in diseases such as cancer. Mutations can have serious clinical implications by increasing kinase catalytic activity or conferring therapeutic resistance. To identify opportunities to repurpose inhibitors against disease-associated mutant kinases, we conducted a large-scale functional screen of 183 known kinase inhibitors against 76 recombinant, mutant kinases. The results revealed lead compounds with activity against clinically important mutant kinases including ALK, LRRK2, RET, and EGFR as well as unexpected opportunities for repurposing FDA-approved kinase inhibitors as leads for additional indications. Furthermore, using T674I PDGFRα as an example, we show how single-dose screening data can provide predictive structure-activity data to guide subsequent inhibitor optimization. This study provides a resource for the development of inhibitors against numerous disease-associated mutant kinases and illustrates the potential of unbiased profiling as an approach to compound-centric inhibitor development.

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“…The specific methods outlined in this protocol for the dot blot kinase assay were used to examine small-molecule inhibition of the insulin receptor kinase domain (11) but these methods can be generalized for examining inhibition of other kinase targets. Reaction conditions such as buffer components, concentration and type of substrates, as well as temperature and time may need to be optimized for kinases other than the insulin receptor kinase.…”

Section: Introductionmentioning

confidence: 99%

“…We perform anion exchange chromatography followed by gel filtration chromatography in order to obtain kinase that is >90% pure by SDS-PAGE. Details of the expression and purification of the insulin receptor kinase can be found in Duong-Ly et al (11) and Wei et al (13). After purification, we store the kinase in small one-time use aliquots at −80°C to preserve catalytic activity.…”

mentioning

confidence: 99%

A High-Throughput Radiometric Kinase Assay

Duong‐Ly

Peterson

2016

Methods in Molecular Biology

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Aberrant kinase signaling has been implicated in a number of diseases. While kinases have become attractive drug targets, only a small fraction of human protein kinases have validated inhibitors. Screening libraries of compounds against a kinase or kinases of interest is routinely performed during kinase inhibitor development to identify promising scaffolds for a particular target and to identify kinase targets for compounds of interest. Screening of more focused compound libraries may also be conducted in the later stages of inhibitor development to improve potency and optimize selectivity. The dot blot kinase assay is a robust, high-throughput kinase assay that can be used to screen a number of small molecule compounds against one kinase of interest or several kinases. Here, a protocol for a dot blot kinase assay used for measuring insulin receptor kinase activity is presented. This protocol can be readily adapted for use with other protein kinases.

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A Highly Selective Dual Insulin Receptor (IR)/Insulin-like Growth Factor 1 Receptor (IGF-1R) Inhibitor Derived from an Extracellular Signal-regulated Kinase (ERK) Inhibitor

Cited by 14 publications

References 42 publications

Reduced Insulin-like Growth Factor I Receptor and Altered Insulin Receptor Isoform mRNAs in Normal Mucosa Predict Colorectal Adenoma Risk

Reduced Insulin-like Growth Factor I Receptor and Altered Insulin Receptor Isoform mRNAs in Normal Mucosa Predict Colorectal Adenoma Risk

Kinase Inhibitor Profiling Reveals Unexpected Opportunities to Inhibit Disease-Associated Mutant Kinases

A High-Throughput Radiometric Kinase Assay

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