title: Structural investigation of B-Raf paradox breaker and inducer inhibitors.
abstract: The V600E missense mutation in B-Raf kinase leads to an anomalous regulation of the MAPK pathway, uncontrolled cell proliferation, and initiation of tumorigenesis. While the ATP-competitive B-Raf inhibitors block the MAPK pathway in B-Raf mutant cells, they induce conformational changes to wild-type B-Raf kinase domain leading to heterodimerization with C-Raf causing a paradoxical hyperactivation of MAPK pathway. A new class of inhibitors (paradox breakers) has been developed that inhibit B-Raf(V600E) activity without agonistically affecting the MAPK pathway in wild-type B-Raf cells. In this study, we explore the structural, conformational, and cellular effects on the B-Raf kinase domain upon binding of paradox breakers and inducers. Our results indicate that a subtle structural difference between paradox inducers and breakers leads to significant conformational differences when complexed with B-Raf. This study provides a novel insight into the activation of B-Raf by ATP-competitive inhibitors and can aid in the design of more potent and selective inhibitors without agonistic function.
authors.affiliation: Institut de Chimie Organique et Analytique, UMR CNRS-Université d'Orléans 7311 , Université d'Orléans BP 6759, Orléans 45067 Cedex 2, France.
authors.forename: Rohit
authors.initials: R
authors.lastname: Arora
authors.forename: Michela
authors.initials: M
authors.lastname: Di Michele
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Stes
authors.forename: Elien
authors.initials: E
authors.lastname: Vandermarliere
authors.forename: Lennart
authors.initials: L
authors.lastname: Martens
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.forename: Erika
authors.initials: E
authors.lastname: Van Heerde
authors.forename: Joannes T M
authors.initials: JT
authors.lastname: Linders
authors.forename: Dirk
authors.initials: D
authors.lastname: Brehmer
authors.forename: Edgar
authors.initials: E
authors.lastname: Jacoby
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonnet
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf