Biological Activity
XL019 is an ATP-binding site-targeting, orally active JAK2 subtype-selective Janus kinase inhibitor (IC50 in nM = 2.2/JAK2 vs. 134.3/JAK1, 214.2/JAK3, 348.3/TYK2) with much reduced or little activity against 116 other kinases (IC50 in nM = 125.4/PDGFRB, 139.7/FLT3, 225.8/c-KIT, 313.8/p70S6K, 370/MLK1, 375.4/IKKbeta, 483.6/KDR, 546.7/PDGFRA, 554.5/FLT4, 910.5/FLT; IC50 >1 μM toward remaining 106 kinases), CYP (1A2, 2C9, 2D6, 3A4 IC50 ≥20 μM), hERG (IC50 = 16 μM), and P-glycoprotein (IC50 >20 μM). XL019 effectively inhibits cellular STAT1/STAT3 phosphorylation both in HEL92.1.7 cultures (IC50 in nM = 386.4/pStat1 and 695/pStat3) and in HEL92.1.7 xenograft-derived tumor in mice in vivo (oral ED50 in mg/kg = 42/pStat1 and 210/pStat3) with significant HEL92.1.7 tumor suppression efficacy in mice (by 60% and 70% on day 14, respectively, with 200 and 300 mg/kg bid p.o. dosage).
