Higher risk of hepatotoxicity associated with cabozantinib in cancer patients

Wang, Zhen; Jiang, Lili; Lv, Xin; Yin, Hang; Wang, Zhe; Li, Wenli; Liu, Yong

doi:10.1016/j.critrevonc.2024.104298

Cited by 2 publications

(2 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5 Compared with other drugs for solid tumors, such as everolimus, sorafenib, sunitinib, paclitaxel et al, cabozantinib is considered to have a higher risk of hepatotoxicity. 35 For fedratinib (a JAK inhibitor; Entry 17), a quinone imine can arise from the 1,4-benzene-amino ether via a labile 4aminophenol if the ether is O-dealkylated. The fourth alert, a benzeneamine that could be para-hydroxylated and then generate quinoids might rank relatively low due to the presence of a hindering sulfonamide group.…”

Section: Conceptmentioning

confidence: 99%

See 1 more Smart Citation

Use of Structural Alerts for Reactive Metabolites in the Application SpotRM

Claesson

2024

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Reactive metabolite (RM) formation is widely accepted as playing a crucial role in causing idiosyncratic adverse drug reactions (IADRs), where the liver is most affected. An important goal of drug design is to avoid selection of drug candidates giving rise to RMs and therefore risk causing problems later on involving IADRs. The simplest, initial approach is to avoid test structures that have substructures known or strongly suspected to be associated with IADRs. However, as is evident from the many case reports of IADRs, in most cases a clear association with any (bio)chemical mechanism is lacking, which makes it hard to establish any structure-toxicity relationship. Separate studies of RM formation, in vitro and in vivo, have led to likely evidence and to establishing many structural alerts (SAs) that can be used for fast selection/deselection of planned test compounds. As a background to a discussion of the concept, 25 kinase inhibitor drugs with known problems of hepatotoxicity were probed against a set of SAs contained in the application SpotRM. A clear majority of the probed drugs show liabilities as evident by being flagged by more than one of the fairly established types of SAs. At the same time, no clear SAs were found in three drugs, which is discussed in the broader context of usefulness and selection tactics of SAs in drug design.

show abstract

Section: Conceptmentioning

confidence: 99%

“…It also has a catechol-like dimethyl ether on an electron-rich quinoline, an obvious liability for RM generation . Compared with other drugs for solid tumors, such as everolimus, sorafenib, sunitinib, paclitaxel et al, cabozantinib is considered to have a higher risk of hepatotoxicity …”

Section: Work To Extend and Improve The Sarm Conceptmentioning

confidence: 99%