Hepatotoxicity of FDA-approved small molecule kinase inhibitors

ABSTRACT

Introduction: Given their importance in cellular processes and association with numerous diseases, protein kinases have emerged as promising targets for drugs. The FDA has approved greater than fifty small molecule kinase inhibitors (SMKIs) since 2001. Nevertheless, severe hepatotoxicity and related fatal cases have grown as a potential challenge in the advancement of these drugs, and the identification and diagnosis of drug-induced liver injury (DILI) are thorny problems for clinicians.

Areas covered: This article summarizes the progression and analyzes the significant features in the study of SMKI hepatotoxicity, including clinical observations and investigations of the underlying mechanisms.

Expert opinion: The understanding of SMKI-associated hepatotoxicity relies on the development of preclinical models and improvement of clinical assessment. With a full understanding of the role of inflammation in DILI and the mediating role of cytokines in inflammation, cytokines are promising candidates as sensitive and specific biomarkers for DILI. The emergence of three-dimensional spheroid models demonstrates potential use in providing clinically relevant data and predicting hepatotoxicity of SMKIs.

KEYWORDS:

• Hepatotoxicity
• small molecule kinase inhibitors
• clinical identification
• underlying mechanisms
• preclinical models

Article highlights

• More than half of the small molecule kinase inhibitors are considered hepatotoxic according to clinical observation, and seven drugs have boxed warning about hepatotoxicity, which is the highest level of warning.

• The underlying mechanisms of SMKI-induced liver injury are partly clarified with the advance of pre-clinical studies, including drug-related properties, mitochodrial toxicity, ihibition of glycolysis, ROS overproduction, GSH depletion, immune-mediated toxicity and host-relatd properties.

• New predictive models of hepatotoxicity associated with small molecule kinase inhibitors have emerged to demonstrate high proliferation capacity and their potential for drug screening experiments.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received personal fees from Novartis from consultancy on drug-induced liver injury with ribociclib. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by National Natural Science Foundation of China (Nos. 81673522 and 81872941) and Science Technology Plan Project of Zhejiang Province (No. 2019C04010).