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Current compound coverage of the kinome.

Ye Hu1, Norbert Furtmann, Jürgen Bajorath

  • 1Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität , Dahlmannstrasse 2, D-53113 Bonn, Germany.

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Summary

Over 19,000 kinase inhibitors targeting half the human kinome are available, though their distribution is uneven. Most are type I, while rare type II inhibitors show high potency.

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Drug Discovery

Background:

  • The human kinome comprises over 500 kinases, crucial regulators of cellular processes.
  • Kinase inhibitors are vital therapeutic agents, particularly in oncology.
  • Understanding the landscape of available kinase inhibitors is essential for drug development.

Purpose of the Study:

  • To comprehensively analyze publicly available kinase inhibitors.
  • To assess the coverage of the human kinome by small molecule inhibitors.
  • To characterize the distribution, types, and promiscuity of kinase inhibitors.

Main Methods:

  • Systematic analysis of a large dataset of publicly available kinase inhibitors.
  • Identification of inhibitors and their corresponding kinase targets.
  • Classification of inhibitors based on type (e.g., type I, type II) and scaffold diversity.
  • Evaluation of inhibitor potency and kinase selectivity.

Main Results:

  • Nearly 19,000 kinase inhibitors targeting 266 kinases (approximately 50% of the human kinome) have been identified.
  • Inhibitor distribution across the kinome is uneven, with a predominance of type I inhibitors.
  • Type II inhibitors are rare but often exhibit high potency.
  • Kinase inhibitors display significant scaffold diversity.
  • Activity cliffs (>=100-fold potency difference) are observed for inhibitors of 106 kinases.
  • Contrary to common assumptions, most inhibitors (>70%) show activity against a single kinase, with only ~1% active against five or more.

Conclusions:

  • A substantial portion of the human kinome is covered by available kinase inhibitors, but their distribution and characteristics vary significantly.
  • The rarity and high potency of type II inhibitors warrant further investigation.
  • Kinase inhibitors are generally more selective than previously thought, with limited polypharmacology for most compounds.
  • This detailed analysis provides a valuable resource for guiding future kinase-targeted drug discovery efforts.