Identification of a novel inhibitor of JAK2 tyrosine kinase by structure-based virtual screening.
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.
Kiss
Róbert
R
Department of Pharmaceutical Chemistry, Semmelweis University, 9 Hogyes Endre u., Budapest H-1092, Hungary.
Polgár
Tímea
T
Kirabo
Annet
A
Sayyah
Jacqueline
J
Figueroa
Nicholas C
NC
List
Alan F
AF
Sokol
Lubomir
L
Zuckerman
Kenneth S
KS
Gali
Meghanath
M
Bisht
Kirpal S
KS
Sayeski
Peter P
PP
Keseru
György M
GM
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
D000475:Alkenes; D050505:Mutant Proteins; D010636:Phenols; D047428:Protein Kinase Inhibitors; D053614:Janus Kinase 2