In vitro
As an inhibitor of Janus kinases, CYT387 can potently inhibit JAK1 and JAK2 with IC50 of 11 and 18 nM, but CYT387 is less potent towards JAK3 with IC50 of 155 nM. CYT387 is a ATP-competitive inhibitor. Researchers tested a list of kinases and conclude Kinase selectivity pro?le of CYT387. For some kinases, CYT387 showed potent inhibition and IC50 is less than 100 nM. They are JAK1, JAK2, CDK2/cyclin A, MAPK8(JNK1), ROCK2, and TBK1. (1) In vitro effects of CYT387 on JAK enzyme activity and on cell lines harboring JAK2, JAK3 or MPL activating mutations. According to this table, CYT387 showed potent inhibition to Ba/F3-MPLW515L, an IL-3 dependent murine pro B cell line with MPL constitutively activated. CYT387 also inhibit IL-3 dependent murine pro B cell lines harboring mutated JAK2 alleles and mutated JAK3 allele, and showed more potent inhibition to cell lines harboring mutated JAK3 alleles. (2) CYT387 inhibits phosphorylation of STAT-5 and STAT-3 in human erythroleukemia (HEL) cells. (3) CYT387 inhibits in vitro erythroid colony formation in polycythemia vera patients: exogenous erythropoietin attenuates this effect. (4) CYT387 caused growth suppression and apoptosis in JAK2-dependent hematopoietic cell lines at the concentration between 0.5 and 1.5muM, while nonhematopoietic cell lines were unaffected. (5) CYT387 was able to prevent IL-6-induced phosphorylation of STAT3 and greatly decrease IL-6- and insulin-like growth factor-1-induced phosphorylation of AKT and extracellular signal-regulated kinase in human myeloma cell lines (HMCL). CYT387 inhibited MM proliferation in a time- and dose-dependent manner in HMCL, and this was not abrogated by the addition of exogenous IL-6. Cell cycling was inhibited with a G(2)/M accumulation of cells, and apoptosis was induced by CYT387 in all HMCL tested.
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