N-&amp;-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine

Bettayeb, Karima; Sallam, Hatem; Ferandin, Yoan; Popowycz, Florence; Fournet, Guy; Hassan, Manal M.; Echalier, Aude; Bernard, Philippe; Endicott, Jane; Joseph, Benoı̂t; Meijer, Laurent

doi:10.1158/1535-7163.mct-08-0080

Cited by 46 publications

(41 citation statements)

References 49 publications

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“…Further more, enhanced apoptosis-inducing effects of N-&-N1 over roscovitine have been observed, probably due to its better kinase selectivity [46]. This work sheds light for the design of second-generation roscovitine analogues, with improved antitumoral efficacy and better PK and pharmacodynamic (PD) profile, thereby circumventing one of the limitations of R-roscovitine.…”

Section: B Preclinical and Clinical Datamentioning

confidence: 76%

Cyclin-dependent kinase inhibitors as potential targeted anticancer agents

2009

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Cyclin-dependent kinases (CDKs) are core components of the cell cycle machinery that govern the transition between phases during cell cycle progression. Genes involved in cell cycle are frequently mutated in human cancer and deregulated CDK activity represents a hallmark of malignancy. This knowledge provides a rationale for regarding CDKs and their associated molecules as potential targets for new drug development in anticancer research. The present article will review the most relevant CDK inhibitors with emphasis on the newer molecules in clinical development and the biological rationale of this therapeutic approach.

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Section: B Preclinical and Clinical Datamentioning

confidence: 76%

Cyclin-dependent kinase inhibitors as potential targeted anticancer agents

2009

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“…Their cellular activity is much weaker, likely due to poor permeability, and they have limited kinase selectivity [243]. The macrocyclic analog 2.75 [244] loses cell-free potency, but gains in terms of cellular penetration.…”

Section: Hsp90-co-chaperone Complexes: Indirect Inhibitionmentioning

confidence: 99%

Targeting the Protein Quality Control (PQC) Machinery

Seneci

2015

Chemical Modulators of Protein Misfolding and Neurodegenerative Disease

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“…However, PDXK was thought to trap (R)-roscovitine and thereby reduce the amount of inhibitor that is free to interact with its main targets. [33] These findings prompted us to investigate the PDXK-C1 interaction in more detail. First, we performed serial affinity chromatography [44,45] to verify a specific enrichment of PDXK by the C1 matrix.…”

Section: Characterization Of the Pyridoxal Kinase-c1 Interactionmentioning

confidence: 99%

“…[32,33] In addition to the expected targets extracellular signal-regulated kinase 1 (ERK1), ERK2, and cyclin-dependent kinases (CDKs), the previously unknown off-target, pyridoxal kinase, was identified. This nonprotein kinase is responsible for the phosphorylation of pyridoxal (PL), pyridoxine (PN) and pyridoxamine (PM) to the respective 5'-phosphate esters PLP, PNP, and PMP, which are the active forms of vitamin B6.…”

Section: Introductionmentioning

confidence: 99%

Off‐Target Decoding of a Multitarget Kinase Inhibitor by Chemical Proteomics

et al. 2009

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Unbiased: Chemical proteomics was used to profile compound interactions in an unbiased fashion. We present here the application of different compound-immobilization routes for decoding nonprotein kinase off-targets of the multitarget kinase inhibitor C1, which interacts with distinct compound moieties. Since the approval of the first selective tyrosine kinase inhibitor, imatinib, various drugs have been developed to target protein kinases. However, due to a high degree of structural conservation of the ATP binding site, off-target effects have been reported for several drugs. Here, we report on off-target decoding for a multitarget protein kinase inhibitor by chemical proteomics, by focusing on interactions with nonprotein kinases. We tested two different routes for the immobilization of the inhibitor on a carrier matrix, and thus identified off-targets that interact with distinct compound moieties. Besides several of the kinases known to bind to the compound, the pyridoxal kinase (PDXK), which has been described to interact with the CDK inhibitor (R)-roscovitine, was captured. The PDXK-inhibitor interaction was shown to occur at the substrate binding site rather than at the ATP binding site. In addition, carbonic anhydrase 2 (CA2) binding was demonstrated, and the determination of the IC(50) revealed an enzyme inhibition in the submicromolar range. The data demonstrate that different compound immobilization routes for chemical proteomics approaches are a valuable method to improve the knowledge about the off-target profile of a compound.

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N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine

Abstract: Cyclin-dependent kinases (CDKs) and their regulators show frequent abnormalities in tumors.

Cited by 46 publications

References 49 publications

Cyclin-dependent kinase inhibitors as potential targeted anticancer agents

Cyclin-dependent kinase inhibitors as potential targeted anticancer agents

Targeting the Protein Quality Control (PQC) Machinery

Off‐Target Decoding of a Multitarget Kinase Inhibitor by Chemical Proteomics

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