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Hepatotoxicity of FDA-approved small molecule kinase inhibitors

Haochen Jiang, Ying Jin, Hao Yan1

  • 1Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou China.

Expert Opinion on Drug Safety
|December 28, 2020
PubMed

Insights

Small molecule kinase inhibitors (SMKIs) show promise but can cause liver injury. New research focuses on understanding SMKI hepatotoxicity mechanisms and developing better diagnostic biomarkers for drug-induced liver injury (DILI).

Area of Science:

  • Pharmacology
  • Hepatology
  • Drug Development

Background:

  • Protein kinases are crucial in cellular functions and disease, making them key drug targets.
  • Over fifty small molecule kinase inhibitors (SMKIs) have been FDA-approved since 2001.
  • Hepatotoxicity and drug-induced liver injury (DILI) present significant challenges in SMKI development and clinical use.

Purpose of the Study:

  • To review the progression and analyze key features of SMKI-induced hepatotoxicity.
  • To investigate the underlying mechanisms of SMKI-associated liver injury.
  • To discuss advancements in preclinical models and clinical assessment for DILI.

Main Methods:

  • Review of clinical observations and case studies related to SMKI hepatotoxicity.
  • Analysis of research investigating the molecular mechanisms of DILI.
  • Evaluation of emerging preclinical models and biomarker strategies for predicting hepatotoxicity.

Main Results:

  • SMKI hepatotoxicity is a growing concern, necessitating improved diagnostic and predictive methods.
  • Inflammation and cytokines play a critical role in DILI pathogenesis.
  • Three-dimensional spheroid models show potential for predicting SMKI-induced liver injury.

Conclusions:

  • Enhanced preclinical models and clinical assessments are vital for understanding SMKI hepatotoxicity.
  • Cytokines are promising biomarkers for sensitive and specific DILI detection.
  • Advanced models like 3D spheroids can provide clinically relevant data for SMKI safety evaluation.
Keywords:
Hepatotoxicityclinical identificationpreclinical modelssmall molecule kinase inhibitorsunderlying mechanisms

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