ABSTRACT
Selectivity remains a challenge for ATP-mimetic kinase inhibitors, an issue that may be overcome by targeting unique residues or binding pockets. However, to date only few strategies have been developed. Here we identify that bulky residues located N-terminal to the DFG motif (DFG-1) represent an opportunity for designing highly selective inhibitors with unexpected binding modes. We demonstrate that several diverse inhibitors exerted selective, non-canonical binding modes that exclusively target large hydrophobic DFG-1 residues present in many kinases including PIM, CK1, DAPK and CLK. Using the CLK family as a model, structural and biochemical data revealed that the DFG-1 valine controlled a non-canonical binding mode in CLK1, providing a rational for selectivity over the closely-related CLK3 which harbors a smaller DFG-1 alanine. Our data suggests that targeting the restricted back pocket in the small fraction of kinases that harbor bulky DFG-1 residues offers a versatile selectivity filter for inhibitor design.
Competing Interest Statement
The authors have declared no competing interest.
ABBREVIATIONS
- CLK
- Cdc2 like kinase
- PIM
- Proviral insertion in murine kinase
- ACVR1
- Activin receptor type I
- DAPK
- death-associated protein kinase
- DYRK
- dual specificity tyrosine-phosphorylation-regulated kinases
- DRAK
- DAP kinase-related apoptosis-inducing protein kinases
- CK
- casein kinase
- RET
- Proto-oncogene tyrosine-protein kinase receptor Ret
- CDK2
- Cyclin-dependent kinase 2
- DFG motif
- tripeptide Asp-Phe-Gly motif
- VIAK motif
- valine-isoleucine-alanine-lysine motif.