Discovery of novel imidazo[1,2-a]pyridines as inhibitors of the insulin-like growth factor-1 receptor tyrosine kinase

Ducray, Richard; Simpson, Iain; Jung, F.; Nissink, J. Willem M.; Kenny, Peter W.; Fitzek, Martina; Walker, Graeme E.; Ward, Lara; Hudson, Kevin

doi:10.1016/j.bmcl.2011.06.093

Cited by 46 publications

(20 citation statements)

References 25 publications

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“…Coincidentally, AstraZeneca has identified a series of similar compounds with an imidazo[1,2-a]pyridine scaffold as IGF-1R inhibitors from a cellular high-throughput screening campaign [52]. Among these, 28 possessed good inhibitory activity in the kinase biochemical assay (IC 50 = 9 nM) and the cellular mechanistic assay (IC 50 = 12 nM), and it also showed good selectivity in the kinase inhibition profile assay except IR, JNK1, JNK2 and ERK8.…”

Section: Imidazopyridinesmentioning

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: Imidazopyridinesmentioning

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

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“…However, confirmation in enzyme assays indicated it was, unsurprisingly, over 1000-fold selective for CDK2 over IGF1R. Nevertheless, a medicinal chemistry programme was initiated to overturn this bias, which, through intensive investigation involving swapping out the sulfonamide group, introduction of an ortho-methoxy group and incorporation of a 5-chloro substituent onto the pyrimidine core, ultimately proved successful and identified compound 25 which had a selective IGF1R profile [57]. Further evolution [58] of this template yielded two candidate drug molecules targeting IGF1R.…”

Section: Selective Inhibitors Of Erbb2 Kinase: Discovery Of Azd3841 Amentioning

confidence: 95%

Standing on the shoulders of giants: a retrospective analysis of kinase drug discovery at AstraZeneca

Kettle

Wilson

2016

Drug Discovery Today

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“…In early 2012, AstraZeneca reported on an imidazo[1,2- a ]pyridine series of IGF-1R/IR inhibitors. 51 , 52 As shown in Figure 10 , compound 22, which emerged from a historical CDK2 program, was identified from an IGF-1R cell-based HTS campaign as a moderate IGF-1R inhibitor. The CDK2 activity was successfully dialed out with the retention of IGF-1R activity as a result of modifications to the aniline pharmacophore (compound 23).…”

Section: Development Of Type I Insulin-like Growth Factor Receptor Inmentioning

confidence: 99%

Modulation of insulin-like growth factor-1 receptor and its signaling network for the treatment of cancer: current status and future perspectives

Jin¹,

Buck²,

Mulvihill³

2013

Oncol Rev

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Based on over three decades of pre-clinical data, insulin-like growth factor-1 receptor (IGF-1R) signaling has gained recognition as a promoter of tumorogenesis, driving cell survival and proliferation in multiple human cancers. As a result, IGF-1R has been pursued as a target for cancer treatment. Early pioneering efforts targeting IGF-1R focused on highly selective monoclonal antibodies, with multiple agents advancing to clinical trials. However, despite some initial promising results, recent clinical disclosures have been less encouraging. Moreover, recent studies have revealed that IGF-1R participates in a dynamic and complex signaling network, interacting with additional targets and pathways thereof through various crosstalk and compensatory signaling mechanisms. Such mechanisms of bypass signaling help to shed some light on the decreased effectiveness of selective IGF-1R targeted therapies (e.g. monoclonal antibodies) and suggest that targeting multiple nodes within this signaling network might be necessary to produce a more effective therapeutic response. Additionally, such findings have led to the development of small molecule IGF-1R inhibitors which also co-inhibit additional targets such as insulin receptor and epidermal growth factor receptor. Such findings have helped to guide the design rationale of numerous drug combinations that are currently being evaluated in clinical trials.

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Discovery of novel imidazo[1,2-a]pyridines as inhibitors of the insulin-like growth factor-1 receptor tyrosine kinase

Cited by 46 publications

References 25 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

Standing on the shoulders of giants: a retrospective analysis of kinase drug discovery at AstraZeneca

Modulation of insulin-like growth factor-1 receptor and its signaling network for the treatment of cancer: current status and future perspectives

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