Metabolic activation of the acrylamide michael acceptor warhead in futibatinib to an epoxide intermediate engenders covalent inactivation of CYP3A was written by Tang, Lloyd Wei Tat;Fu, Jiaxin;Koh, Siew Kwan;Wu, Guoyi;Zhou, Lei;Chan, Eric Chun Yong. And the article was included in Drug Metabolism & Disposition in 2022.Formula: C26H31Cl2N7O3 This article mentions the following:
Futibatinib (FUT) is a potent inhibitor of fibroblast growth factor receptor (FGFR) 1-4 that is currently under clin. investigation for intrahepatic cholangiocarcinoma. Unlike its predecessors, FUT possesses an acrylamide warhead, which enables it to bind covalently to a free cysteine residue in the FGFR kinase domain. However, it remains uninterrogated if this electrophilic α,β-unsaturated carbonyl scaffold could also directly or indirectly engender offtarget covalent binding to nucleophilic centers on other cellular proteins. Here, we discovered that FUT inactivated both CYP3A isoforms with inactivator concentration at half-maximum inactivation rate constant, maximum inactivation rate constant, and partition ratios of 12.5 and 51.4 μM, 0.25 and 0.06 min-1, and ~52 and ~58 for CYP3A4 and CYP3A5, resp. Along with its time-, concentration-, and cofactor-dependent inhibitory profiles, FUT also exhibited several cardinal features that were consistent with mechanism-based inactivation. Moreover, the nature of inactivation was unlikely to be pseudo-irreversible and instead arose from the covalent modification of the cytochrome P 450 apoprotein and/or its heme moiety due to the lack of substantial enzyme activity recovery following dialysis and chem. oxidation, as well as the absence of the diagnostic Soret peak in spectral analyses. Finally, utilizing glutathione (GSH) trapping and high-resolution mass spectrometry, we illuminated that while the acrylamide moiety in FUT could nonenzymically conjugate to GSH via Michael addition, it was not implicated in the covalent inactivation of CYP3A. Rather, we surmised that it likely stemmed from the metabolic activation of its acrylamide covalent warhead to a highly electrophilic epoxide intermediate that could covalently modify CYP3A and culminate in its catalytic inactivation. SIGNIFICANCE STATEMENT In this study, we reported for the first time the inactivation of CYP3A by futibatinib (FUT). Furthermore, using FUT as an exemplary targeted covalent inhibitor, our study revealed the propensity for its acrylamide Michael acceptor moiety to be metabolically activated to a highly electrophilic epoxide. Due to the growing resurgence of covalent inhibitors and the well-established toxicol. ramifications associated with epoxides, we advocate that closer scrutiny be adopted when profiling the reactive metabolites of compounds possessing an α,β-unsaturated carbonyl scaffold. In the experiment, the researchers used many compounds, for example, 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea (cas: 872511-34-7Formula: C26H31Cl2N7O3).
3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea (cas: 872511-34-7) belongs to piperazine derivatives. Piperazine belongs to the family of medicines called anthelmintics. Piperazine and its salts did not induce point mutations in a bacterial test. A series of mutagenicity studies in cells, both in vitro and in vivo, has been completed and showed no evidence of mutagenic effect.Formula: C26H31Cl2N7O3
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Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics