RAF kinases [Elektronische Ressource] : pathway, modulation and modeling / vorgelegt von Armin Robubi

RAF Kinases: Pathway, Modulation andModelingDissertation zur Erlangung des naturwissenschaftlichenDoktorgrades der Bayerischen Julius-Maximilians-Universit atWurzburgvorgelegt vonArmin RobubiausTeheran, IranWurzburg 2007Eingereicht am:Mitglieder der Promotionskommission:Vorsitzender: Prof. Dr. Martin J. MullerGutachter : Prof. Dr. Thomas Dandekarhter: Prof. Dr. Ulf R. RappTag des Promotionskolloquiums:Doktorurkunde ausgeh andigt am:RAF Kinases: Pathway, Modulation andModelingArmin RobubiDepartment of BioinformaticsUniversity of WurzburgDecember 12, 2007I dedicate this work to my mother.Plain question and plain answer make the shortest road out ofmost perplexities.Mark TwainAbstractThe Ras/RAF/MEK/ERK cascade is a central cellular signal transductionpathway involved in cell proliferation, di erentiation, and survival where RAFkinases are pivotal kinases implicated in cancer.The development of speci c irreversible kinase inhibitors is a rewardingbut di cult aim. CI-1033 was developed to irreversibly inhibit erbB recep-tor tyrosine kinases by reacting to the Cys113 residue (p38 MAP kinasenumbering) of the kinase domain. In this study we tried a similar approachto target the RAF oncoproteins which posses a similar cysteine at position108 in the hinge region between the small n-lobe and the large c-lobe of thekinase domain.