title: A general framework for inhibitor resistance in protein kinases.
abstract: Protein kinases control virtually every aspect of normal and pathological cell physiology and are considered ideal targets for drug discovery. Most kinase inhibitors target the ATP binding site and interact with residue of a hinge loop connecting the small and large lobes of the kinase scaffold. Resistance to kinase inhibitors emerges during clinical treatment or as a result of in vitro selection approaches. Mutations conferring resistance to ATP site inhibitors often affect residues that line the ATP binding site and therefore contribute to selective inhibitor binding. Here, we show that mutations at two specific positions in the hinge loop, distinct from the previously characterized "gatekeeper," have general adverse effects on inhibitor sensitivity in six distantly related kinases, usually without consequences on kinase activity. Our results uncover a unifying mechanism of inhibitor resistance of protein kinases that might have widespread significance for drug target validation and clinical practice.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Deborah
authors.initials: D
authors.lastname: Balzano
authors.forename: Stefano
authors.initials: S
authors.lastname: Santaguida
authors.forename: Andrea
authors.initials: A
authors.lastname: Musacchio
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Villa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D004351:Drug Resistance; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D014372:Tubercidin / Q000031:analogs & derivatives / Q000494:pharmacology; D019061:src-Family Kinases
chemical_list: D047428:Protein Kinase Inhibitors; C034214:5-iodotubercidin; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D014372:Tubercidin