Abstract
7083 Background: The molecular pathogenesis of the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocytosis, and myelofibrosis with myeloid metaplasia has been conclusively linked to an activating mutation of JAK2 (Janus Associated Kinase 2). In addition, aberrant activation of the JAK-STAT pathway has been implicated in the etiology of other human cancers due to activation of JAK2 by excessive cytokines and silencing of SOCs, a negative regulator of JAK-STAT signaling. In order to address this unmet clinical need TG101348 was designed and synthesized as a potent inhibitor of JAK2 that is highly selectivity against undesirable off-target kinases, including 332X, 135X and 35 selectivity versus JAK3, Tyk2 and JAK1, respectively as well as potently inhibiting less than 2% of the kinases evaluated in a commercially available, phylogenetically diverse panel of 223 kinases. Methods: TG101348 was evaluated for its capacity to block aberrant cell proliferation and reverse JAK2-induced clini...
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