A fluorescence anisotropy-based Myt1 kinase binding assay

Assay Drug Dev Technol. 2014 Mar;12(2):136-44. doi: 10.1089/adt.2013.534. Epub 2013 Nov 14.

Abstract

Abstract The human Myt1 kinase is a regulator of Cdk1/CycB and, hence, important for the G2/M transition in the cell cycle. It may act as a target for drug development, but suitable assay systems for assessing potential inhibitors are lacking so far. Herein, we describe the rational development of a fluorescence anisotropy-based kinase binding assay. A suitable fluoroprobe based on the tyrosine kinase inhibitor dasatinib was synthesized and tested with Myt1 and several other kinases for control purposes. The probe acted as expected in terms of specificity and reversibility, and a Myt1 assay was set up. Notwithstanding the moderate Kd of the starting compound dasatinib before chemical modification, satisfying Z' factors >0.5 were achieved. A validation with known kinase inhibitors demonstrated the applicability of the assay and led to a reliable ranking of the tested active compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray / methods*
  • Dasatinib
  • Dose-Response Relationship, Drug
  • Fluorescence Polarization / methods*
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism*
  • Protein Binding / physiology
  • Protein Serine-Threonine Kinases / chemistry*
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / chemistry*
  • Protein-Tyrosine Kinases / metabolism*
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism
  • Thiazoles / chemistry
  • Thiazoles / metabolism

Substances

  • Membrane Proteins
  • Pyrimidines
  • Thiazoles
  • Protein-Tyrosine Kinases
  • PKMYT1 protein, human
  • Protein Serine-Threonine Kinases
  • Dasatinib