In Vitro and Reactive Metabolites Investigation of Metabolic Profiling of Tyrosine Kinase Inhibitors Dubermatinib in HLMs by LC–MS/MS
Dubermatinib (DMB, TP-0903), a benzenesulfonamide, is an inhibitor of the tyrosine kinase AXL, which is a member of the TAM family and can prevent GAS6-mediated activation of AXL in cancer cells. Patients with previously treated chronic lymphocytic leukemia are being studied in phase I/II clinical t...
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MDPI AG
2023-06-01
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| author | Nasser S. Al-Shakliah Adnan A. Kadi Hatem A. Abuelizz Rashad Al-Salahi |
| author_facet | Nasser S. Al-Shakliah Adnan A. Kadi Hatem A. Abuelizz Rashad Al-Salahi |
| author_sort | Nasser S. Al-Shakliah |
| collection | DOAJ |
| description | Dubermatinib (DMB, TP-0903), a benzenesulfonamide, is an inhibitor of the tyrosine kinase AXL, which is a member of the TAM family and can prevent GAS6-mediated activation of AXL in cancer cells. Patients with previously treated chronic lymphocytic leukemia are being studied in phase I/II clinical trials to determine its antineoplastic potential (CLL). In the current work, the Xenosite web predictor tool was employed to predict the vulnerable sites of metabolism and the reactivity pathways (cyanide and GSH) of DMB. Subsequently, we present the analysis and identification of in vitro and reactive intermediates of DMB using liquid chromatography ion trap mass spectrometry (LC–ITMS). Human liver microsomes (HLMs) were exposed to dimethylbenzene in a laboratory setting, and the resulting metabolites were collected through protein precipitation. Intense reactivity toward nucleophilic macromolecules was seen in the metabolites of the piperazine and pyrimidine rings in DMB, iminium, and 2,5-quinone-imine, respectively. To assess the toxicities of the possibly reactive metabolites, DMB was incubated with HLMs in the presence of 1.0 mM KCN and 1.0 mM glutathione. The DMB metabolites found by LC–MS/MS were seven in vitro phase I metabolites, three cyano adducts, and two GSH conjugates. Phase I in vitro metabolic reactions included <i>N</i>-demethylation, hydroxylation, and dechlorination. DMB and its metabolites have not been investigated for their metabolism in vitro. |
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| issn | 2297-8739 |
| language | English |
| last_indexed | 2024-03-11T01:56:24Z |
| publishDate | 2023-06-01 |
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| spelling | doaj.art-c93d31b63fb7461d8e1fe1c432825a592023-11-18T12:36:22ZengMDPI AGSeparations2297-87392023-06-0110635310.3390/separations10060353In Vitro and Reactive Metabolites Investigation of Metabolic Profiling of Tyrosine Kinase Inhibitors Dubermatinib in HLMs by LC–MS/MSNasser S. Al-Shakliah0Adnan A. Kadi1Hatem A. Abuelizz2Rashad Al-Salahi3Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDubermatinib (DMB, TP-0903), a benzenesulfonamide, is an inhibitor of the tyrosine kinase AXL, which is a member of the TAM family and can prevent GAS6-mediated activation of AXL in cancer cells. Patients with previously treated chronic lymphocytic leukemia are being studied in phase I/II clinical trials to determine its antineoplastic potential (CLL). In the current work, the Xenosite web predictor tool was employed to predict the vulnerable sites of metabolism and the reactivity pathways (cyanide and GSH) of DMB. Subsequently, we present the analysis and identification of in vitro and reactive intermediates of DMB using liquid chromatography ion trap mass spectrometry (LC–ITMS). Human liver microsomes (HLMs) were exposed to dimethylbenzene in a laboratory setting, and the resulting metabolites were collected through protein precipitation. Intense reactivity toward nucleophilic macromolecules was seen in the metabolites of the piperazine and pyrimidine rings in DMB, iminium, and 2,5-quinone-imine, respectively. To assess the toxicities of the possibly reactive metabolites, DMB was incubated with HLMs in the presence of 1.0 mM KCN and 1.0 mM glutathione. The DMB metabolites found by LC–MS/MS were seven in vitro phase I metabolites, three cyano adducts, and two GSH conjugates. Phase I in vitro metabolic reactions included <i>N</i>-demethylation, hydroxylation, and dechlorination. DMB and its metabolites have not been investigated for their metabolism in vitro.https://www.mdpi.com/2297-8739/10/6/353<i>N</i>-methyl piperazineDubermatinibin vitro metabolitescyano adductsGSH conjugateXenosite reactivity model |
| spellingShingle | Nasser S. Al-Shakliah Adnan A. Kadi Hatem A. Abuelizz Rashad Al-Salahi In Vitro and Reactive Metabolites Investigation of Metabolic Profiling of Tyrosine Kinase Inhibitors Dubermatinib in HLMs by LC–MS/MS Separations <i>N</i>-methyl piperazine Dubermatinib in vitro metabolites cyano adducts GSH conjugate Xenosite reactivity model |
| title | In Vitro and Reactive Metabolites Investigation of Metabolic Profiling of Tyrosine Kinase Inhibitors Dubermatinib in HLMs by LC–MS/MS |
| title_full | In Vitro and Reactive Metabolites Investigation of Metabolic Profiling of Tyrosine Kinase Inhibitors Dubermatinib in HLMs by LC–MS/MS |
| title_fullStr | In Vitro and Reactive Metabolites Investigation of Metabolic Profiling of Tyrosine Kinase Inhibitors Dubermatinib in HLMs by LC–MS/MS |
| title_full_unstemmed | In Vitro and Reactive Metabolites Investigation of Metabolic Profiling of Tyrosine Kinase Inhibitors Dubermatinib in HLMs by LC–MS/MS |
| title_short | In Vitro and Reactive Metabolites Investigation of Metabolic Profiling of Tyrosine Kinase Inhibitors Dubermatinib in HLMs by LC–MS/MS |
| title_sort | in vitro and reactive metabolites investigation of metabolic profiling of tyrosine kinase inhibitors dubermatinib in hlms by lc ms ms |
| topic | <i>N</i>-methyl piperazine Dubermatinib in vitro metabolites cyano adducts GSH conjugate Xenosite reactivity model |
| url | https://www.mdpi.com/2297-8739/10/6/353 |
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