Discovery and optimization of narrow spectrum inhibitors of Tousled like kinase 2 (TLK2) using quantitative structure activity relationships

Eur J Med Chem. 2024 May 5:271:116357. doi: 10.1016/j.ejmech.2024.116357. Epub 2024 Apr 2.

Abstract

The oxindole scaffold has been the center of several kinase drug discovery programs, some of which have led to approved medicines. A series of two oxindole matched pairs from the literature were identified where TLK2 was potently inhibited as an off-target kinase. The oxindole has long been considered a promiscuous kinase inhibitor template, but across these four specific literature oxindoles TLK2 activity was consistent, while the kinome profile was radically different ranging from narrow to broad spectrum kinome coverage. We synthesized a large series of analogues, utilizing quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites, kinome profiling, and small-molecule x-ray structural analysis to optimize TLK2 inhibition and kinome selectivity. This resulted in the identification of several narrow spectrum, sub-family selective, chemical tool compounds including 128 (UNC-CA2-103) that could enable elucidation of TLK2 biology.

Keywords: Kinase chemical tool; Kinase inhibitors; Oxindole; Quantitative structure-activity relationship (QSAR); Tousled like kinase 2 (TLK2).

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Oxindoles / chemical synthesis
  • Oxindoles / chemistry
  • Oxindoles / pharmacology
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Quantitative Structure-Activity Relationship*

Substances

  • Protein Kinase Inhibitors
  • Oxindoles
  • Protein Serine-Threonine Kinases