Characterization of Irreversible Kinase Inhibitors by Directly Detecting Covalent Bond Formation: A Tool for Dissecting Kinase Drug Resistance

Klüter, Sabine; Simard, Jeffrey R.; Rode, Haridas B.; Grütter, Christian; Pawar, Vijaykumar G.; Raaijmakers, H.C.A.; Barf, Tjeerd; Rabiller, Matthias; Otterlo, Willem A. L. van; Rauh, Daniel

doi:10.1002/cbic.201000352

Cited by 42 publications

(39 citation statements)

References 132 publications

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“…These results are also in agreement with predicted electrophilicity of vinyl sulfonamides and α-chloro ketones. 23 Compounds 8 and 9 are the most potent inhibitors of T338M c-Src reported to date and demonstrate the ability of irreversible kinase inhibitors to effectively inhibit mutant kinases with resistance to their reversible counterparts.…”

Section: Resultsmentioning

confidence: 99%

Irreversible Inhibitors of c-Src Kinase That Target a Nonconserved Cysteine

et al. 2012

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We have developed the first irreversible inhibitors of wild-type c-Src kinase. We demonstrate that our irreversible inhibitors display improved potency and selectivity relative to their reversible counterparts. Our strategy involves modifying a promiscuous kinase inhibitor with an electrophile to generate covalent inhibitors of c-Src. We applied this methodology to two inhibitor scaffolds that exhibit increased cellular efficacy when rendered irreversible. In addition, we have demonstrated the utility of irreversible inhibitors in studying the conformation of an important loop in kinases that can control inhibitor selectivity and cause drug resistance. Together, we have developed a general and robust framework for generating selective irreversible inhibitors from reversible, promiscuous inhibitor scaffolds.

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Section: Resultsmentioning

confidence: 99%

Irreversible Inhibitors of c-Src Kinase That Target a Nonconserved Cysteine

et al. 2012

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“…In particular, quinazoline and quinoline fluorophores had been shown to significantly enhance fluorescence emission after covalent reaction with Cys797 of EGFR-TK. 58 Thus, the 3-aminopropanamide 5 was added to a buffered solution containing EGFR-TK (see the Experimental Section and Figure 2A for details), samples were excited at 390 nm, and fluorescence emission at 420 nm was monitored over time. The results were compared to those of the irreversible 3 and the reversible N-(4-(3-bromoanilino)-quinazolin-6-yl)acetamide 64 (46) (Figure 2B).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

et al. 2012

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Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with offtargets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.

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“…However, their use in the clinic has a long tradition of success, and several voices have recently defended their use (55). Indeed, a variety of approaches have been followed by different groups to design either irreversible or covalently bound kinase inhibitors with therapeutic potential as a strategy to overcome drug resistance (56) or to improve the selectivity of the inhibition (57). Although the currently available data do not prove unequivocally the covalent binding of tideglusib to GSK-3␤, the irreversible inhibition it causes becomes more relevant when considering the slow turnover rate of GSK-3␤ in neuronal cells.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3β by Tideglusib

Domínguez¹,

Fuertes²,

Orozco³

et al. 2012

Journal of Biological Chemistry

206

141

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Background: Tideglusib is a GSK-3 inhibitor currently undergoing clinical trials for Alzheimer disease and progressive supranuclear palsy. Results: Removal of unbound compound does not recover the enzyme activity, and the dissociation rate constant is close to zero. The protein shows a low turnover rate in neurons. Conclusion: Tideglusib is an irreversible inhibitor of GSK-3␤. Significance: The irreversibility and the long enzyme half-life may possess interesting pharmacodynamic implications.

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Characterization of Irreversible Kinase Inhibitors by Directly Detecting Covalent Bond Formation: A Tool for Dissecting Kinase Drug Resistance

Cited by 42 publications

References 132 publications

Irreversible Inhibitors of c-Src Kinase That Target a Nonconserved Cysteine

Irreversible Inhibitors of c-Src Kinase That Target a Nonconserved Cysteine

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3β by Tideglusib

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