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Updated: Jan 30, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

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Integrative identification of unexpected kinase-inhibitor interactions in the MAPK-mediated proliferation and

Lei Zhao1, Qun Huang, Shoujin Tian

  • 1Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China. qironggdong@sina.cn.

General Physiology and Biophysics
|January 19, 2019
PubMed

Insights

Kinase inhibitors can harm bone growth by affecting osteoblasts. This study found Dasatinib unexpectedly targets the MAPK pathway in osteoblasts, posing a skeletal risk.

Area of Science:

  • Pharmacology
  • Cell Biology
  • Biochemistry

Background:

  • Kinase-targeted therapies offer promise but can cause skeletal adverse effects.
  • Osteoblast proliferation and differentiation are regulated by the MAPK signaling pathway.
  • Off-target kinase inhibitor interactions may disrupt this crucial pathway.

Purpose of the Study:

  • To investigate unexpected mitogen-activated protein kinase (MAPK) inhibitor interactions in mouse osteoblastic cells.
  • To identify specific kinase inhibitors with potential off-target effects on the MAPK pathway.
  • To assess the risk posed by these interactions to osteoblast function.

Main Methods:

  • Utilized an integrative protocol combining bioinformatics analysis and experimental validation.
  • Performed systematic profiling of noncognate interactions between kinase inhibitors and mouse MAPK kinases.
  • Assessed cytotoxicity and inhibitory activity of candidate inhibitors in MC3T3-E1 cells.

Main Results:

  • Identified 13 potential MAPK-inhibitor interactions, with Nilotinib, Dasatinib, and Bosutinib as promising candidates.
  • Dasatinib demonstrated significant cytotoxicity in MC3T3-E1 cells.
  • Dasatinib was confirmed to unexpectedly target the osteoblast MAPK signaling pathway.

Conclusions:

  • Dasatinib presents a high off-target risk due to its unexpected interaction with the osteoblast MAPK pathway.
  • This finding highlights the importance of evaluating kinase inhibitors for skeletal safety.
  • Further research is needed to understand and mitigate these adverse effects.

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