Characterization of covalent binding of tyrosine kinase inhibitors to plasma proteins. Issue 5 (October 2020)

• Record Type: Journal Article
• Authors: Liu, Xiaoyun; Feng, Dan; Zheng, Mingyue; Cui, Yongmei; Zhong, Dafang
• Is Part Of: Drug metabolism and pharmacokinetics. Volume 35:Issue 5(2020)
• Page Start: 456
• Page End: 465
• Publication Date: 2020-10
• Subjects: Covalent tyrosine kinase inhibitors -- Covalent binding -- Human serum albumin -- Molecular docking -- Quantitative calculations -- Linear modeling -- Species difference; Drugs -- Metabolism -- Periodicals; Pharmacokinetics -- Periodicals; 615.7
• DOI: 10.1016/j.dmpk.2020.07.002
• Languages: English
• ISSNs: 1347-4367

Abstract

Abstract: Eight covalent tyrosine kinase inhibitors (TKIs) were investigated to determine the characteristics of their covalent binding to plasma proteins. The data revealed that their covalent binding to plasma proteins is of species difference. In addition to the reports on neratinib and pyrotinib, osimertinib, alflutinib, AST5902, and ibrutinib were confirmed to covalently bind to the Lys-190 of human serum albumin (HSA). Molecular docking was used to simulate the binding mode of TKIs to HSA. The results exhibited the non-covalent interactions between covalent TKIs and HSA, which stabilize the TKIs-HSA complex and explain the selectivity of covalent binding. The t 1/2 values of TKIs that are covalently bound to HSA or human plasma proteins were studied in vitro, and the features highly correlated with the t 1/2 were determined by quantitative calculations and linear modeling. Reversibility of the covalent binding and the factors affecting the process of reversibility were evaluated. In conclusion, acrylamide moiety of covalent TKIs can covalently bind to lysine residue of HSA, most of which were determined to be Lys-190. The covalent binding is of species difference, especially between animal and human. Except for osimertinib, covalent binding between TKIs and HSA are reversible. Graphical abstract: Image 1