Aurora Isoform Selectivity: Design and Synthesis of Imidazo[4,5-<i>b</i>]pyridine Derivatives as Highly Selective Inhibitors of Aurora-A Kinase in Cells

Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Perez‐Fuertes, Yolanda; Schmitt, Jessica; Boxall, Kathy; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine L.; Henley, Alan T.; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian

doi:10.1021/jm401115g

Cited by 71 publications

(37 citation statements)

References 47 publications

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“…Functionalized pyridoimidazoles remained difficult to synthesize, even with the development of C À H functionalization methods. [10] However, as shown in Scheme 3, pyridoimidazoles could easily be prepared through the electrolysis of 4and 3-aminopyridine-derived substrates. In particular, the products when using the latter (5 d-k) were formed with excellent regioselectivity (see the Supporting Information for…”

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confidence: 99%

Amidinyl Radical Formation through Anodic N−H Bond Cleavage and Its Application in Aromatic C−H Bond Functionalization

et al. 2016

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We report herein an atom-economical and sustainable approach to access amidinyl radical intermediates through the anodic cleavage of N-H bonds. The resulting nitrogen-centered radicals undergo cyclizations with (hetero)arenes, followed by rearomatization, to afford functionalized tetracyclic benzimidazoles in a highly straightforward and efficient manner. This metal- and reagent-free C-H/N-H cross-coupling reaction exhibits a broad substrate scope and proceeds with high chemoselectivity.

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confidence: 99%

Amidinyl Radical Formation through Anodic N−H Bond Cleavage and Its Application in Aromatic C−H Bond Functionalization

et al. 2016

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“…Nevertheless, the rationale for selective Aurora isoform inhibition vs pan-Aurora inhibition remains unclear and the ideal inhibitor profile has yet to be established. 5,28 In Vivo Studies. Compound 47 was evaluated in different tumor models and showed significant efficacy in mice bearing the human acute myeloid leukemia EOL-1 and the human colon adenocarcinoma HCT116 xenografted subcutaneously (data not shown).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

SAR156497, an Exquisitely Selective Inhibitor of Aurora Kinases

Carry¹,

Clerc²,

Minoux³

et al. 2014

J. Med. Chem.

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The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.

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“…Several Aurora kinase inhibitors have been identified as excellent antitumor inhibitors. Recently, it has been reported that a series of imidazo [4,5-b]pyridine derivatives possess excellent potencies as orally bioavailable Aurora A inhibitors [7,8].…”

Section: Introductionmentioning

confidence: 99%

High‐dimensional QSAR prediction of anticancer potency of imidazo[4,5‐b]pyridine derivatives using adjusted adaptive LASSO

Algamal

Lee

Al-Fakih

et al. 2015

Journal of Chemometrics

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In high-dimensional quantitative structure-activity relationship (QSAR) studies, identifying relevant molecular descriptors is a major goal. In this study, a proposed penalized method is used as a tool for molecular descriptors selection. The method, called adjusted adaptive least absolute shrinkage and selection operator (LASSO) (AALASSO), is employed to study the high-dimensional QSAR prediction of the anticancer potency of a series of imidazo[4,5-b]pyridine derivatives. This proposed penalized method can perform consistency selection and deal with grouping effects simultaneously. Compared with other commonly used penalized methods, such as LASSO and adaptive LASSO with different initial weights, the results show that AALASSO obtains the best predictive ability not only by consistency selection but also by encouraging grouping effects in selecting more correlated molecular descriptors. Hence, we conclude that AALASSO is a reliable penalized method in the field of high-dimensional QSAR studies.

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Aurora Isoform Selectivity: Design and Synthesis of Imidazo[4,5-b]pyridine Derivatives as Highly Selective Inhibitors of Aurora-A Kinase in Cells

Cited by 71 publications

References 47 publications

Amidinyl Radical Formation through Anodic N−H Bond Cleavage and Its Application in Aromatic C−H Bond Functionalization

Amidinyl Radical Formation through Anodic N−H Bond Cleavage and Its Application in Aromatic C−H Bond Functionalization

SAR156497, an Exquisitely Selective Inhibitor of Aurora Kinases

High‐dimensional QSAR prediction of anticancer potency of imidazo[4,5‐b]pyridine derivatives using adjusted adaptive LASSO

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