The Landscape of Atypical and Eukaryotic Protein Kinases

Trends Pharmacol Sci. 2019 Nov;40(11):818-832. doi: 10.1016/ Epub 2019 Oct 31.


Kinases are attractive anticancer targets due to their central role in the growth, survival, and therapy resistance of tumor cells. This review explores the two primary kinase classes, the eukaryotic protein kinases (ePKs) and the atypical protein kinases (aPKs), and provides a structure-centered comparison of their sequences, structures, hydrophobic spines, mutation and SNP hotspots, and inhibitor interaction patterns. Despite the limited sequence similarity between these two classes, atypical kinases commonly share the archetypical kinase fold but lack conserved eukaryotic kinase motifs and possess altered hydrophobic spines. Furthermore, atypical kinase inhibitors explore only a limited number of binding modes both inside and outside the orthosteric binding site. The distribution of genetic variations in both classes shows multiple ways they can interfere with kinase inhibitor binding. This multilayered review provides a research framework bridging the eukaryotic and atypical kinase classes.

Keywords: SNP; catalytic kinase domain structures; eukaryotic and atypical protein kinases; oncogenic mutations; selective kinase inhibitor design; small-molecule kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Humans
  • Models, Molecular
  • Neoplasms / drug therapy
  • Neoplasms / enzymology*
  • Neoplasms / genetics
  • Polymorphism, Single Nucleotide
  • Protein Conformation, beta-Strand
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / chemistry
  • Protein Kinases / classification*
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Protein Kinases