title: Identification of a novel inhibitor of JAK2 tyrosine kinase by structure-based virtual screening.
abstract: Janus kinase 2 (JAK2) plays a crucial role in the pathomechanism of myeloproliferative disorders and hematologic malignancies. A somatic mutation of JAK2 (Val617Phe) was previously shown to occur in 98% of patients with polycythemia vera and 50% of patients with essential thrombocythemia and primary myelofibrosis. Thus, effective JAK2 kinase inhibitors may be of significant therapeutic importance. Here, we applied a structure-based virtual screen to identify novel JAK2 inhibitors. One JAK2 inhibitor in particular, G6, demonstrated remarkable potency as well as specificity, which makes it as a potential lead candidate against diseases related to elevated JAK2 tyrosine kinase activity.
authors.affiliation: Department of Pharmaceutical Chemistry, Semmelweis University, 9 Hogyes Endre u., Budapest H-1092, Hungary.
authors.forename: Róbert
authors.initials: R
authors.lastname: Kiss
authors.forename: Tímea
authors.initials: T
authors.lastname: Polgár
authors.forename: Annet
authors.initials: A
authors.lastname: Kirabo
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Sayyah
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Figueroa
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
authors.forename: Lubomir
authors.initials: L
authors.lastname: Sokol
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Zuckerman
authors.forename: Meghanath
authors.initials: M
authors.lastname: Gali
authors.forename: Kirpal S
authors.initials: KS
authors.lastname: Bisht
authors.forename: Peter P
authors.initials: PP
authors.lastname: Sayeski
authors.forename: György M
authors.initials: GM
authors.lastname: Keseru
mesh_terms: D000475:Alkenes / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000475:Alkenes; D050505:Mutant Proteins; D010636:Phenols; D047428:Protein Kinase Inhibitors; D053614:Janus Kinase 2