title: Targeting gain of function and resistance mutations in Abl and KIT by hybrid compound design.
abstract: Mutations in the catalytic domain at the gatekeeper position represent the most prominent drug-resistant variants of kinases and significantly impair the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular and atomic levels will aid in the design and development of inhibitors that have the potential to overcome these resistance mutations. Herein, by introducing adaptive elements into the inhibitor core structure, we undertake the structure-based development of type II hybrid inhibitors to overcome gatekeeper drug-resistant mutations in cSrc-T338M, as well as clinically relevant tyrosine kinase KIT-T670I and Abl-T315I variants, as essential targets in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). Using protein X-ray crystallography, we confirm the anticipated binding mode in cSrc, which proved to be essential for overcoming the respective resistances. More importantly, the novel compounds effectively inhibit clinically relevant gatekeeper mutants of KIT and Abl in biochemical and cellular studies.
authors.affiliation: Department of Chemistry and Chemical Biology, Technical University of Dortmund, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Richters
authors.forename: Julia
authors.initials: J
authors.lastname: Ketzer
authors.forename: Matthäus
authors.initials: M
authors.lastname: Getlik
authors.forename: Christian
authors.initials: C
authors.lastname: Grütter
authors.forename: Ralf
authors.initials: R
authors.lastname: Schneider
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Heuckmann
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heynck
authors.forename: Martin L
authors.initials: ML
authors.lastname: Sos
authors.forename: Anu
authors.initials: A
authors.lastname: Gupta
authors.forename: Anke
authors.initials: A
authors.lastname: Unger
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz-Fademrecht
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bauer
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
mesh_terms: D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D016315:Proto-Oncogene Proteins c-abl