Development of Narrow Spectrum ATP-competitive Kinase Inhibitors as Probes for BIKE and AAK1

Abstract

Understanding the structural determinants of inhibitor selectivity would 18 facilitate the design and preparation of kinase probes. We describe a pair of matched 19 compounds differing only by one degree of saturation but showing dramatic differential 20 activities at select kinases. We utilized x-ray crystallography and computational analysis 21 to rationalize the basis of the differential activity. 22

The Landscape of Atypical and Eukaryotic Protein Kinases

“…Note that throughout this review we utilize the KLIFS i residue nomenclature for the 85 residues defining the binding cleft (see Figure I in Box 2) [34,35] whenever applicable (e.g., F linker. 50 refers to a phenylalanine at KLIFS position 50 of the binding site, which is located in the linker segment).…”

“…However, in all of the mentioned kinases there is an alternative cluster of hydrophobic residues in that region that interacts with the other residues of the C-spine. Only RIOK1 and ADCK3 are similar to the ePKs, as they have an aF-helix with hydrophobic residues at the conserved positions [50]. It should be noted that hydrophobic mutations in or surrounding the hydrophobic spines have been shown to affect kinase regulation with potential oncogenic effects [51].…”

“…This inhibitor is over 200 times more selective for PI3Kg than the other isoforms [83] due to the small hydrophobic A linker. 50 . In all other isoforms, the slightly bigger and polar serine at the same position prevents the inhibitor from assuming this binding mode.…”

Integration of Phenotypic Drug Efficacy and Molecular Chemogenomics Data

“…However, in all of the mentioned kinases there is an alternative cluster of hydrophobic residues in that region that interacts with the other residues of the C-spine. Only RIOK1 and ADCK3 are similar to the ePKs as they have αF-helix with hydrophobic residues at the conserved positions [369]. It should be noted that hydrophobic mutations in or surrounding the hydrophobic spines have been shown to affect kinase regulation with potential oncogenic effects [370].…”