Characterization of HKI-272 Covalent Binding to Human Serum Albumin
作者： Jianyao Wang , Xiao Xian Li-Chan , Jim Atherton , Lin Deng , Robert Espina
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摘要: The study was initiated as an observation of incomplete extraction recovery N-(4-(3-chloro-4-(2-pyridinylmethoxy)anilino)-3-cyano-7-ethoxy-6-quinolyl)-4-(dimethylamino)-2-butenamide (HKI-272) from human plasma. objective this to 1) identify the binding site(s) HKI-272 plasma protein(s); 2) characterize nature binding; and 3) evaluate potential reversibility covalent binding. After incubation [(14)C]HKI-272 with plasma, mixture directly injected on liquid chromatography/mass spectrometry (LC/MS), intact molecular mass serum albumin (HSA) adduct determined be 66,999 Da, which is 556 Da (molecular HKI-272) larger than measured HSA (66,443 Da). For peptide mapping, separated SDS-polyacrylamide gel electrophoresis followed by tryptic digestion combined LC/tandem MS. A radioactive fragment, LDELRDEGKASSAK [amino acid (AA) residue 182-195 albumin], confirmed covalently bind HKI-272. In addition, after HCl hydrolysis, a HKI-272-lysine identified LC/MS. combining results AA Lys190 standard synthesized characterized NMR. data showed that formed via Michael addition epsilon-amine lysine attacking beta-carbon amide moiety Furthermore, shown when gradual release observed protein pellet HKI-272-treated resuspension in phosphate buffer, pH 7.4, at 37 degrees C for 18 h.
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