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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

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Published on: December 7, 2014

Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase

Wooyoung Hur1, Anastasia Velentza, Sungjoon Kim

  • 1Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.

Bioorganic & Medicinal Chemistry Letters
|August 1, 2008
PubMed

Insights

Irreversible HER/erbB inhibitors target a unique cysteine in kinases. These inhibitors also potently inhibit the Tec-family kinase Bmx, suggesting potential clinical cross-reactivity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Irreversible inhibitors targeting HER/erbB kinases exploit a unique cysteine residue in the ATP-binding pocket.
  • Sequence analysis reveals this cysteine is conserved in other kinase families, including the Tec-family.

Purpose of the Study:

  • To investigate the potential cross-reactivity of irreversible HER/erbB inhibitors with other kinase families.
  • To determine if the Tec-family kinase Bmx is inhibited by these agents.

Main Methods:

  • Sequence alignment of protein kinases to identify conserved cysteine residues.
  • In vitro assays to assess the inhibitory activity of clinical-stage EGFR inhibitors against Bmx.

Main Results:

  • A rare cysteine residue, crucial for irreversible HER/erbB inhibition, is present in ten other protein kinases, including all five Tec-family members.
  • The Tec-family kinase Bmx is potently inhibited by irreversible modification at Cys496 using clinical-stage EGFR inhibitors like CI-1033.

Conclusions:

  • Irreversible HER/erbB inhibitors exhibit cross-reactivity with the Tec-family kinase Bmx.
  • This cross-reactivity has potential significant clinical implications for targeted cancer therapy.

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