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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
10:49

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Published on: September 18, 2013

Protein tyrosine kinase inhibitors as novel therapeutic agents

A Levitzki1

  • 1Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Israel.

Pharmacology & Therapeutics
|August 24, 1999
PubMed

Insights

Tyrosine phosphorylation inhibitors (tyrphostins) selectively target protein tyrosine kinases (PTKs) implicated in proliferative diseases. These tyrphostins show promise as targeted cancer and anti-inflammatory therapies.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Protein tyrosine kinases (PTKs) are crucial for cell development.
  • Dysregulated PTK activity is linked to proliferative diseases like cancer and psoriasis.
  • Targeting PTKs offers a therapeutic strategy for these conditions.

Purpose of the Study:

  • To systematically synthesize and evaluate tyrosine phosphorylation inhibitors (tyrphostins) as potential therapeutic agents.
  • To develop selective tyrphostins targeting specific receptor and non-receptor tyrosine kinases.
  • To assess the in vivo efficacy of synthesized tyrphostins in disease models.

Main Methods:

  • Systematic synthesis of a library of tyrphostins.
  • In vitro kinase inhibition assays to determine selectivity.
  • In vivo studies in animal models to evaluate therapeutic efficacy.

Main Results:

  • Demonstrated ability to synthesize selective tyrphostins against various PTKs.
  • AG 490 (Jak-2 inhibitor) showed potency against pre-B acute lymphoblastic leukemia.
  • AG 1295 (PDGFR inhibitor) reduced stenosis in pigs; AG 1517 (EGFR inhibitor) and SU 5416 (VEGFR inhibitor) are in clinical trials for psoriasis and cancer, respectively.
  • Tyrphostins exhibited efficacy in inflammatory disease models (sepsis, cirrhosis, EAE).

Conclusions:

  • Targeting specific PTKs involved in disease pathogenesis can lead to effective drug development.
  • Tyrphostins represent a promising class of drugs with demonstrated efficacy in preclinical and clinical studies for cancer and inflammatory conditions.
  • The development of selective tyrphostins offers a viable strategy for treating a range of proliferative and inflammatory diseases.

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