Discovery of an inhibitor of insulin-like growth factor 1 receptor activation: Implications for cellular potency and selectivity over insulin receptor

Wood, Edgar R.; Shewchuk, Lisa M.; Hassel, Anne; Nichols, Jim; Truesdale, Anne T.; Smith, D.R; Carter, H. Luke; Weaver, K.; Barrett, George B.; Leesnitzer, Tony; Alvarez, Emilio; Bardera, Ana Isabel; Alamillo, Amelia; Cantizani, Juan; Martin, Joseph V.; Smith, Gary K.; Jensen, David E.; Xie, Hongbo; Mook, Robert A.; Kumar, Rakesh; Kuntz, Kevin W.

doi:10.1016/j.bcp.2009.07.022

Cited by 8 publications

(6 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In these regards, small-molecule tyrosine kinase domain inhibitors (TKI) of IGF-1R, which are under investigation in clinical trials, could be a better strategy to target IGF-1R/IR signaling, as IGF-1R monoclonal antibody induced a compensatory increase of IR phosphorylation, which could be abolished by IGF-1R TKI 32 . A challenge to the development of IGF-1R-targeted kinase inhibitors may be the similarity of the catalytic domain to that of the IR 33–35 . Inhibition of the IR in normal cells could have brought significant undesired effects on glucose homeostasis, and chronic treatment may result in symptoms of diabetes 36 .…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of insulin receptor expression on survival of patients with nonsmall cell lung cancer

Kim

Liu

Lee

et al. 2011

Cancer

View full text Add to dashboard Cite

Background The purpose of this study was to characterize insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) expression in patients with non-small cell lung cancer (NSCLC). Methods A total of 459 patients who underwent curative resection of NSCLC were studied (median follow-up duration, 4.01 years). Expression of the IR and IGF-1R protein in tumor specimens was assessed immunohistochemically using tissue microarrays. Results The cytoplasmic IR score was higher in patients with adenocarcinoma (ADC) than in those with squamous cell carcinoma (SCC) whereas cytoplasmic IGF-1R score was higher in patients with SCC than those with ADC. Neither IR nor IGF-1R expression was associated with sex, smoking history, or clinical stage. Patients with positive IR or IGF-1R expression levels had poor recurrence-free (RFS) (3.8 vs. 3.3 years; 3.8 vs. 2.0 years, respectively), but similar overall survival (OS). Patients with high expression levels of IR and IGF-1R had shorter RFS and OS compared to those with low levels of IR and/or IGF-1R expression. Finally, a multivariate analysis revealed the impact of IR, but not of IGF-1R, as an independent predictive marker of NSCLC survival: hazard ratio (HR) for OS, 1.005 (95% confidence interval [CI], 1.001 – 1.010], HR for RFS, 1.005 (95% CI, 1.001 – 1.009), when IR score was tested as a continuous variable. Conclusions Overexpression of IR predicts a poor survival among patients with NSCLC, especially those with SCC. These results might serve as future guidance to the clinical trials involving IR or IGR-1R targeting agents.

show abstract

Section: Discussionmentioning

confidence: 99%

Prognostic impact of insulin receptor expression on survival of patients with nonsmall cell lung cancer

Kim

Liu

Lee

et al. 2011

Cancer

View full text Add to dashboard Cite

show abstract

“…IGF-1R antibodies block ligand binding and induce receptor internalization and degradation [14], also resulting in insulin receptor (InsR) downregulation in cells expressing IGF-1R:InsR hybrid receptors [23]. The majority of IGF-1R TKIs described to date act by competing with ATP for binding in the IGF-1R kinase domain [18,20,24], and also inhibit InsR due to conservation of structure, particularly in the ATP-binding cleft of the kinase domain [25]. As a class effect, IGF-1R inhibitory drugs cause hyperglycemia, although this is usually mild and reversible [6,26].…”

Section: Igf-targeting: a Promising Startmentioning

confidence: 99%

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

King

Aleksic

Haluska

et al. 2014

Cancer Treatment Reviews

122

132

View full text Add to dashboard Cite

IGF-1R inhibitors arrived in the clinic accompanied by optimism based on preclinical activity of IGF-1R targeting, and recognition that low IGF bioactivity protects from cancer. This was tempered by concerns about toxicity to normal tissue IGF-1R and cross-reactivity with insulin receptor (InsR). In fact, toxicity is not a show-stopper; the key issue is efficacy. While IGF-1R inhibition induces responses as monotherapy in sarcomas and with chemotherapy or targeted agents in common cancers, negative Phase 2/3 trials in unselected patients prompted the cessation of several Pharma programs. Here, we review completed and on-going trials of IGF-1R antibodies, kinase inhibitors and ligand antibodies. We assess candidate bio-markers for patient selection, highlighting the potential predictive value of circulating IGFs/IGFBPs, the need for standardized assays for IGF-1R, and preclinical evidence that variant InsRs mediate resistance to IGF-1R antibodies. We review hypothesis-led and unbiased approaches to evaluate IGF-1R inhibitors with other agents, and stress the need to consider sequencing with chemotherapy. The last few years were a tough time for IGF-1R therapeutics, but also brought progress in understanding IGF biology. Even failed studies include patients who derived benefit; they should be investigated to identify features distinguishing the tumors and host environment of responders from non-responders. We emphasize the importance of incorporating biospecimen collection into trial design, and wording patient consents to allow post hoc analysis of trial material as new data become available. Such information represents the key to unlocking the potential of this approach, to inform the next generation of trials of IGF signalling inhibitors.

show abstract

“…Purine analog 30 was identified from a high-throughout screening of the GSK compound collection as a moderate IGF-1R inhibitor to suppress the substrate phosphorylation (IC 50 = 3300 nM) with equipotent inhibitory activity against the IR (IC 50 = 4000 nM) [54]. But interestingly, the compound was potent and selective for IGF-1-mediated IGF-1R autophosphorylation versus the IR autophosphorylation in intact cells, IC 50 values of which were 110 nM and 2994 nM respectively.…”

Section: Purinesmentioning

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

View full text Add to dashboard Cite

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.

show abstract

Discovery of an inhibitor of insulin-like growth factor 1 receptor activation: Implications for cellular potency and selectivity over insulin receptor

Cited by 8 publications

References 44 publications

Prognostic impact of insulin receptor expression on survival of patients with nonsmall cell lung cancer

Prognostic impact of insulin receptor expression on survival of patients with nonsmall cell lung cancer

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

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

Contact Info

Product

Resources

About