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The Landscape of Atypical and Eukaryotic Protein Kinases

Georgi K Kanev1, Chris de Graaf2, Iwan J P de Esch2

  • 1Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands; Department of Neurosurgery, Amsterdam University Medical Centers, Cancer Center Amsterdam, Brain Tumor Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

Trends in Pharmacological Sciences
|November 4, 2019
PubMed

Insights

This review compares eukaryotic and atypical protein kinases, revealing structural differences that impact drug development. Understanding these kinase classes offers a new framework for anticancer drug discovery.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • Kinases are crucial regulators of cell growth, survival, and drug resistance in cancer.
  • Eukaryotic protein kinases (ePKs) and atypical protein kinases (aPKs) represent two major kinase classes with therapeutic potential.

Purpose of the Study:

  • To provide a structure-centered comparison of ePKs and aPKs.
  • To explore sequence, structure, mutation hotspots, and inhibitor interactions.
  • To establish a research framework bridging these kinase classes for anticancer drug development.

Main Methods:

  • Comparative analysis of kinase sequences and structures.
  • Examination of hydrophobic spine alterations.
  • Mapping of mutation and single nucleotide polymorphism (SNP) hotspots.
  • Analysis of kinase inhibitor binding modes.

Main Results:

  • Limited sequence similarity exists between ePKs and aPKs, though aPKs often retain the archetypical kinase fold.
  • aPKs lack conserved eukaryotic kinase motifs and exhibit altered hydrophobic spines.
  • Atypical kinase inhibitors utilize a restricted set of binding modes.
  • Genetic variations in both kinase classes can impede inhibitor binding.

Conclusions:

  • Structural and sequence differences between ePKs and aPKs influence inhibitor interactions.
  • Understanding these variations is key to developing effective anticancer therapies targeting kinases.
  • This review offers a unified research perspective for both kinase classes.
Keywords:
SNPcatalytic kinase domain structureseukaryotic and atypical protein kinasesoncogenic mutationsselective kinase inhibitor designsmall-molecule kinase inhibitors

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