Structural identification of imatinib cyanide adducts by mass spectrometry and elucidation of bioactivation pathway

Li, Austin C.; Yu, Erya; Ring, Steven C.; Chovan, James P.

doi:10.1002/rcm.6758

Cited by 16 publications

(31 citation statements)

References 22 publications

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“…Though KCN is not a common trapping agent for soft electrophiles, its formation was proposed to occur through dehydration of hydroxymethyl derivative 27 to a p ‐imine‐methide RM 28 (Figure ). Otherwise, this soft electrophile did not lead to a GSH adduct, presumably because of steric hindrance issues . These results are in accordance with those of Kenny et al who also evidenced cyanide but not GSH adducts.…”

Section: Tki Metabolic Activation: Evidence Of Rm Formationsupporting

confidence: 92%

“…The hydroxylation of the methyl group on the p ‐toluidine moiety has been described in many reports . A cyanide adduct 29 was evidenced . Though KCN is not a common trapping agent for soft electrophiles, its formation was proposed to occur through dehydration of hydroxymethyl derivative 27 to a p ‐imine‐methide RM 28 (Figure ).…”

Section: Tki Metabolic Activation: Evidence Of Rm Formationmentioning

confidence: 84%

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Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

Paludetto

Puisset

Chatelut

et al. 2019

Medicinal Research Reviews

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Tyrosine kinase inhibitors (TKI) are small heterocyclic molecules targeting transmembrane and cytoplasmic tyrosine kinases that have met with considerable success in clinical oncology. TKI are associated with toxicities including liver injury that may be serious and even life‐threatening. Many of them require warnings in drug labeling against liver injury, and five of them have Black Box Warning (BBW) labels. Although drug‐induced liver injury is a matter of clinical and industrial concern, little is known about the underlying mechanisms that likely involve reactive metabolites (RM). RM are electrophiles or radicals originating from the metabolic activation of particular functional groups, known as structural alerts or toxicophores. RM are able to covalently bind to proteins and macromolecules, causing cellular damage and even cell death. If the adducted protein is the enzyme involved in RM formation, time‐dependent inhibition of the enzyme—also called mechanism‐based inhibition (MBI) or inactivation—can occur and lead to pharmacokinetic drug‐drug interactions. To mitigate RM liabilities, common practice in drug development includes avoiding structural alerts and assessing RM formation via RM trapping screens with soft and hard nucleophiles (glutathione, potassium cyanide, and methoxylamine) in liver microsomes. RM‐positive derivatives are further optimized to afford drug candidates with blocked or minimized bioactivation potential. However, different structural alerts are still commonly used scaffolds in drug design, including in TKI structures. This review focuses on the current state of knowledge of the relations among TKI structures, bioactivation pathways, RM characterization, and hepatotoxicity and cytochrome P450 MBI in vitro.

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Section: Tki Metabolic Activation: Evidence Of Rm Formationsupporting

confidence: 92%

Section: Tki Metabolic Activation: Evidence Of Rm Formationmentioning

confidence: 84%

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

Paludetto

Puisset

Chatelut

et al. 2019

Medicinal Research Reviews

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“…More recently, Zhao et al described a novel bioactivation pathway of erlotinib mediated by CYP3A4 and CYP3A5 to form a reactive ketene intermediate, which was trapped as an adduct with 4-bromobenzylamine [31]. In addition to these tyrosine kinase inhibitors, imatinib [20], axitinib [21], ponatinib [22], and sunitinib [23], have been shown to undergo bioactivation to form reactive metabolites, which were trapped as stable adducts. Recent findings regarding the bioactivation mechanisms of these tyrosine kinase inhibitors will be discussed below.…”

Section: Bioactivation Of Small Molecule Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

“…In the study by Kenny et al, seven cyanide conjugates and one methoxylamine conjugate were observed from liver microsomal incubations in vitro [26]. Li et al, characterized the bioactivation of imatinib at the piperizine ring to form imine and imine–carbonyl (α,β-unsaturated) intermediates, and bioactivation of the p -toluidine moiety to form imine–methide intermediates trapped as cyanide adducts [20]. …”

Section: Bioactivation Of Small Molecule Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

“…This topic has been reviewed, with excellent articles by Duckett and Cameron, [11] Stepan et al [13] and Teo et al [14] Reactive metabolites have been identified for the following clinically available tyrosine kinase inhibitors: dasitinib [15], gefitinib [16]. erlotinib [17], lapatinib [18,19], imatinib [20], axitinib [21], ponatinib [22], sunitinib [23], as well as investigational tyrosine kinase inhibitors. The purpose of the present review is to (1) provide updates on recently characterized bioactivation mechanisms of selected tyrosine kinase inhibitors, (2) discuss progress towards elucidating the cellular mechanisms of hepatocellular injury related to tyrosine kinase inhibitors, and (3) briefly discuss recent findings related to risk factors of tyrosine kinase inhibitor-induced hepatotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Role of Cytochrome P450 Enzymes in the Metabolic Activation of Tyrosine Kinase Inhibitors

Jackson

Durandis

2018

IJMS

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Tyrosine kinase inhibitors are a rapidly expanding class of molecular targeted therapies for the treatment of various types of cancer and other diseases. An increasing number of clinically important small molecule tyrosine kinase inhibitors have been shown to undergo cytochrome P450-mediated bioactivation to form chemically reactive, potentially toxic products. Metabolic activation of tyrosine kinase inhibitors is proposed to contribute to the development of serious adverse reactions, including idiosyncratic hepatotoxicity. This article will review recent findings and ongoing studies to elucidate the link between drug metabolism and tyrosine kinase inhibitor-associated hepatotoxicity.

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Detection and characterization of olmutinib reactive metabolites by LC–MS/MS: Elucidation of bioactivation pathways

Attwa

Kadi

2019

J of Separation Science

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Olmutinib (Olita™) is an orally bioavailable third generation epidermal growth factor receptor tyrosine kinase inhibitor. Olmutinib was approved in South Korea in May 2016 for the treatment of patients suffering from locally advanced or metastatic epidermal growth factor receptor T790M mutation‐positive non‐small cell lung cancer. Reactive olmutinib intermediates may be responsible for the severe side effects associated with the treatment. However, literature review revealed no previous reports on the structural identification of reactive olmutinib metabolites. In this work, the formation of reactive olmutinib metabolites in rat liver microsomes was investigated. Methoxylamine, glutathione, and potassium cyanide were used as capturing agents for aldehyde, iminoquinones, and iminium intermediates, respectively. The stable complexes formed were identified using liquid chromatography–tandem mass spectrometry. The major phase I metabolic pathway observed in vitro was hydroxylation of the piperazine ring. Seven potential reactive intermediates were characterized, including three iminium ions, three iminoquinones, and one aldehyde. Based on the findings, various bioactivation pathways were postulated. Hence, identifying the reactive intermediates of olmutinib that may be the cause of severe side effects can provide new insights, leading to improved treatments for patients.

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Structural identification of imatinib cyanide adducts by mass spectrometry and elucidation of bioactivation pathway

Abstract: Chemical structures of seven cyanide adducts of imatinib have been identified or proposed based on high-resolution MS/MS data. Mechanisms for the formation of the conjugates were also proposed. The findings may help to understand the mechanism of hepatotoxicity of imatinib in humans.

Cited by 16 publications

References 22 publications

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

Role of Cytochrome P450 Enzymes in the Metabolic Activation of Tyrosine Kinase Inhibitors

Detection and characterization of olmutinib reactive metabolites by LC–MS/MS: Elucidation of bioactivation pathways

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