Abstract
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.
Original language | English |
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Pages (from-to) | 818-832 |
Number of pages | 15 |
Journal | Trends in Pharmacological Sciences |
Volume | 40 |
Issue number | 11 |
Early online date | 31 Oct 2019 |
DOIs | |
Publication status | Published - Nov 2019 |
Funding
This work is supported by a grant of the Amsterdam Academic Alliance (Amsterdam Data Science) as provided by the Boards of the VU and UvA universities, and by the Cancer Center Amsterdam - project CCA2018-2-19 .
Keywords
- catalytic kinase domain structures
- eukaryotic and atypical protein kinases
- oncogenic mutations
- selective kinase inhibitor design
- small-molecule kinase inhibitors
- SNP