Chemical modification of the tyrosine kinase inhibitor (TKI) imatinib was performed to obtain the imatinib-N-oxide, followed by metabolic profiling to study the possibilities of forming potential reactive metabolites of both imatinib and imatinib-N-oxide. The structure of the N-oxide metabolite was elucidated using various spectrometric techniques, including mass spectrometry, and nuclear magnetic resonance analysis. Metabolic profiling and the potential for reactive metabolite formation were investigated for both imatinib and the synthesized imatinib-N-oxide using rat liver microsomes and three chemical trapping agents (potassium cyanide, methoxylamine, and glutathione). Identification and characterization of the metabolites and any reactive metabolites were performed using an Agilent 6320 ion trap mass spectrometer. The results showed that imatinib-N-oxide produced two dihydroxy metabolites. Importantly, no reactive metabolites were observed for either imatinib or the imatinib-N-oxide in the presence of the chemical trapping agents. These findings contribute to the understanding of the metabolic fate and reactive metabolite potential of the TKI imatinib and its N-oxide metabolite, which is valuable information for assessing the safety and toxicological profile of this important oncology drug.
SupuranCTScozzafavaA. Protein tyrosine kinase inhibitors as anticancer agents. Expert Opin Ther Pat2004; 14: 35–53.
2.
TraxlerP. Tyrosine kinases as targets in cancer therapy – successes and failures. Expert Opin Ther Targets2003; 7: 215–234.
3.
BhullarKSLagarónNOMcGowanEM, et al.Kinase-targeted cancer therapies: progress, challenges and future directions. Mol Cancer2018; 17: 48.
4.
AlanaziMMMahdyHAAlsaifNA, et al.New bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, in silico studies, and anticancer evaluation. Bioorg Chem2021; 112: 104949.
5.
AlanaziMMElkadyHAlsaifNA, et al.New quinoxaline-based VEGFR-2 inhibitors: design, synthesis, and antiproliferative evaluation with in silico docking, ADMET, toxicity, and DFT studies. RSC Adv2021; 11: 30315–30328.
6.
AlanaziMMElkadyHAlsaifNA, et al.Discovery of new quinoxaline-based derivatives as anticancer agents and potent VEGFR-2 inhibitors: design, synthesis, and in silico study. J Mol Struct2022; 1253: 132220.
7.
AlanaziMMEissaIHAlsaifNA, et al.Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers. J Enzyme Inhib Med Chem2021; 36: 1760–1782.
8.
BhanumathyKKBalagopalAVizeacoumarFS, et al.Protein tyrosine kinases: their roles and their targeting in leukemia. Cancers (Basel)2021; 13: 184. DOI:10.3390/cancers13020184
9.
Sudhesh DevSZainal AbidinSAFarghadaniR, et al.Receptor tyrosine kinases and their signaling pathways as therapeutic targets of curcumin in cancer. Front Pharmacol2021; 12: 772510.
10.
HuangLJiangSShiY. Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001–2020). J Hematol Oncol2020; 13: 143.
11.
MartinKAndreasH. Recent advances in the development of multi-kinase inhibitors. Mini-rev med Chem2008; 8: 1312–1327.
12.
RewcastleGWDennyWABridgesAJ, et al.Tyrosine kinase inhibitors. 5. Synthesis and structure-activity relationships for 4-[(phenylmethyl)amino]- and 4-(phenylamino)quinazolines as potent adenosine 5′-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor. J Med Chem1995; 38: 3482–3487.
13.
ChenCShiQXuJ, et al.Current progress and open challenges for applying tyrosine kinase inhibitors in osteosarcoma. Cell Death Discov2022; 8: 88.
14.
YesilkanalAEJohnsonGLRamosAF, et al.New strategies for targeting kinase networks in cancer. J Biol Chem2021; 297: 101128.
15.
von MansteinVYangCMRichterD, et al.Resistance of cancer cells to targeted therapies through the activation of compensating signaling loops. Curr Signal Transduct Ther2013; 8: 193–202.
16.
NiederstMJEngelmanJA. Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci Signal2013; 6: re6.
17.
ZhangRHGuoHYDengH, et al.Piperazine skeleton in the structural modification of natural products: a review. J Enzyme Inhib Med Chem2021; 36: 1165–1197.
18.
ZhangNNAnBJZhouY, et al.Synthesis, evaluation, and mechanism study of new tepotinib derivatives as antiproliferative agents. Molecules2019; 24: 1173.
19.
FaroukFShammaR. Chemical structure modifications and nano-technology applications for improving ADME-Tox properties, a review. Arch Pharm2019; 352: 1800213.
20.
LimbanCNuţăDCChiriţăC, et al.The use of structural alerts to avoid the toxicity of pharmaceuticals. Toxicol Rep2018; 5: 943–953.
21.
ChaMYKangSJKimMR, et al.Novel fused pyrimidine derivatives for inhibition of tyrosine kinase activity. Patent WO/2011/162515, Korea, 2011.
22.
BotrusGRamanPOliverT, et al.Infigratinib (BGJ398): an investigational agent for the treatment of FGFR-altered intrahepatic cholangiocarcinoma. Expert Opin Invest Drugs2021; 30: 309–316.
23.
LiaoBCLinCCLeeJH, et al.Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors. J Biomed Sci2016; 23: 86.
24.
Meneses-LorenteGFowlerSGueriniE, et al.In vitro and clinical investigations to determine the drug-drug interaction potential of entrectinib, a small molecule inhibitor of neurotrophic tyrosine receptor kinase (NTRK). Invest New Drugs2022; 40: 68–80.
25.
ZhangYCChenZHZhangXC, et al.Analysis of resistance mechanisms to abivertinib, a third-generation EGFR tyrosine kinase inhibitor, in patients with EGFR T790M-positive non-small cell lung cancer from a phase I trial. EBioMedicine2019; 43: 180–187.
26.
AhangariFBeckerCFosterDG, et al.Saracatinib, a selective Src kinase inhibitor, blocks fibrotic responses in preclinical models of pulmonary fibrosis. Am J Respir Crit Care Med2022; 206: 1463–1479.
27.
NinomiyaKOhashiKMakimotoG, et al.MET Or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib. Sci Rep2018; 8: 1955.
28.
LathamBDOskinDSCrouchRD, et al.Cytochromes P450 2C8 and 3A catalyze the metabolic activation of the tyrosine kinase inhibitor Masitinib. Chem Res Toxicol2022; 35: 1467–1481.
29.
ZhaoJQuanHXuY, et al.Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants. Cancer Sci2014; 105: 117–125.
30.
BaekYYSungBChoiJS, et al.In vivo efficacy of Imatinib mesylate, a tyrosine kinase inhibitor, in the treatment of chemically induced dry eye in animal models. Transl Vis Sci Technol2021; 10: 14.
31.
Marcos-JiménezACarvoeiroDCRuefN, et al.Dasatinib-induced spleen contraction leads to transient lymphocytosis. Blood Adv2023; 7: 2418–2430.
32.
PonnurangamSStandingDRangarajanP, et al.Tandutinib inhibits the Akt/mTOR signaling pathway to inhibit colon cancer growth. Mol Cancer Ther2013; 12: 598–609.
33.
DiPeriTPEvansKWRasoMG, et al.Adavosertib enhances antitumor activity of trastuzumab deruxtecan in HER2-expressing cancers. Clin Cancer Res2023; 29: 4385–4398.
34.
ChoHJHwangJAYangEJ, et al.Nintedanib induces senolytic effect via STAT3 inhibition. Cell Death Dis2022; 13: 760.
35.
Al-ShakliahNSKadiAAAljoharHI, et al.Profiling of in vivo, in vitro and reactive zorifertinib metabolites using liquid chromatography ion trap mass spectrometry. RSC Adv2022; 12: 20991–21003.
36.
Al-ShakliahNSAttwaMWAlRabiahH, et al.Identification and characterization of in vitro, in vivo, and reactive metabolites of tandutinib using liquid chromatography ion trap mass spectrometry. Anal Methods2021; 13: 399–410.
37.
RahmanAFMMAl-ShakliahNSYinW, et al.In vitro investigation of metabolic profiling of a potent topoisomerase inhibitors fluorescein hydrazones (FLHs) in RLMs by LC-MS/MS. J Chromatogr B2017; 1054: 27–35.
38.
LowryOHRosebroughNJFarrAL, et al.Protein measurement with the Folin phenol reagent. J Biol Chem1951; 193: 265–275.
39.
BillingsRE. Sex differences in rats in the metabolism of phenytoin to 5-(3,4-dihydroxyphenyl)-5-phenylhydantoin. J Pharmacol Exp Ther1983; 225: 630–636. Research Support, U.S. Gov't, P.H.S. 1983/06/01.
40.
AdattiniJAGrossASWong DooN, et al.Real-world efficacy and safety outcomes of imatinib treatment in patients with chronic myeloid leukemia: an Australian experience. Pharmacol Res Perspect2022; 10: e01005.
41.
KnightGWMcLellanD. Use and limitations of imatinib mesylate (Glivec), a selective inhibitor of the tyrosine kinase Abl transcript in the treatment of chronic myeloid leukaemia. Br J Biomed Sci2004; 61: 103–111.
42.
AlvesRGonçalvesACRutellaS, et al.Resistance to tyrosine kinase inhibitors in chronic Myeloid Leukemia-from molecular mechanisms to clinical relevance. Cancers (Basel)2021; 13. DOI:10.3390/cancers13194820
43.
ShahNPTranCLeeFY, et al.Overriding Imatinib resistance with a novel ABL kinase inhibitor. Science2004; 305: 399–401.
44.
JabbourEKantarjianHCortesJ. Use of second- and third-generation tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia: an evolving treatment paradigm. Clinical Lymphoma Myeloma and Leukemia2015; 15: 323–334.
45.
MughalTISchrieberA. Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase. Biologics2010; 4: 315–323.
46.
SalemWHoJRWooI, et al.Long-term imatinib diminishes ovarian reserve and impacts embryo quality. J Assist Reprod Genet2020; 37: 1459–1466.
47.
Imatinib Side Effects. In: drugs.com, (ed.). 2024.
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