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DFG-1 residue controls inhibitor binding mode and affinity providing a basis for rational design of kinase inhibitor selectivity

DOI: 10.1021/acs.jmedchem.0c00898 DOI Help

Authors: Martin Schroeder (Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe-University Frankfurt) , Alex N. Bullock (Structural Genomics Consortium, University of Oxford) , Oleg Fedorov (Structural Genomics Consortium, University of Oxford) , Franz Bracher (Ludwig-Maximilians University Munich) , Apirat Chaikuad (Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe-University Frankfurt) , Stefan Knapp (Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe-University Frankfurt; German Translational Cancer Network (DKTK))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: August 2020
Diamond Proposal Number(s): 442

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.

Journal Keywords: kinase inhibitors; inhibitor selectivity; structure-based design; DFG-1 residue; xDFG

Subject Areas: Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography

Other Facilities: BESSY II; SLS