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A High-Throughput Method for Measuring Drug Residence Time Using the Transcreener ADP Assay.

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This summary is machine-generated.

Drug-target residence time analysis improves drug development. A new high-throughput screening (HTS)-compatible assay accurately measures dissociation rates (koff) for kinase inhibitors, aiding early-stage drug discovery.

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Drug Discovery

Background:

  • Drug-target residence time is crucial for optimizing drug efficacy and safety.
  • Traditional methods for measuring dissociation rates (koff) are often low-throughput and not amenable to automation.
  • A need exists for high-throughput screening (HTS)-compatible assays to assess drug-target interactions early in discovery.

Purpose of the Study:

  • To adapt a jump dilution catalytic assay for determining koff values in an HTS environment.
  • To establish a universal, homogenous assay for measuring kinase inhibitor dissociation rates.
  • To facilitate the use of residence time for compound prioritization in kinase drug discovery.

Main Methods:

  • Adapted a classic "jump dilution" catalytic assay for koff determination.
  • Utilized the Transcreener ADP2 Kinase assay to monitor kinase activity recovery after drug dissociation.
  • Employed fluorescence polarization (FP), fluorescence intensity (FI), and time-resolved Förster resonance energy transfer (TR-FRET) detection modes.

Main Results:

  • Successfully measured residence times for kinase inhibitors targeting EGFR, ABL1, and Aurora kinases.
  • The rank ordering of inhibitor koff values correlated well with literature data from ligand binding assays.
  • Consistent results were observed across FP, FI, and TR-FRET detection modes.

Conclusions:

  • Developed an HTS-compatible, generic assay for measuring drug-target dissociation rates.
  • This assay method enables early assessment of residence time for kinase inhibitors.
  • Facilitates compound prioritization and optimization in early kinase drug discovery programs.