title: Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc.
abstract: The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.
authors.affiliation: Chemical Genomics Centre of the Max Planck Society, D-44227 Dortmund, Germany.
authors.forename: Matthäus
authors.initials: M
authors.lastname: Getlik
authors.forename: Christian
authors.initials: C
authors.lastname: Grütter
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Simard
authors.forename: Sabine
authors.initials: S
authors.lastname: Klüter
authors.forename: Matthias
authors.initials: M
authors.lastname: Rabiller
authors.forename: Haridas B
authors.initials: HB
authors.lastname: Rode
authors.forename: Armin
authors.initials: A
authors.lastname: Robubi
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
mesh_terms: D000495:Allosteric Site; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D022001:Focal Adhesions / Q000187:drug effects; D006801:Humans; D020125:Mutation, Missense; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D019061:src-Family Kinases
chemical_list: D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D014508:Urea; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human