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- W2079803213 abstract "Activation of JAK2, an intracellular protein tyrosine kinase, is known to induce cell proliferation and apoptosis and it has been shown to be mediated by pro‐inflammatory cytokines. JAK2 dysregulation is implicated in myeloproliferative disorders, solid tumor malignancies, and autoimmune diseases. Utilizing our proprietary CLIMB™ technology, a computationally driven drug discovery process, we have rapidly designed and developed, SGI‐1252, a potent oral inhibitor which exhibits low nanomolar in vitro activity against all of the JAK kinase family, except JAK3. Additionally, it has low nanomolar activity against ALK2, a high‐affinity binding receptor for bone morphogenic protein. As predicted from computational models, SGI‐1252 is well tolerated across several rodent species and demonstrates a wide safety margin in both short‐ and long‐term toxicity studies. Acute maximum tolerated doses of greater than 900 mg/kg are observed in mice and rats dosed orally with SGI‐1252. Over a 5‐week period, daily oral dosing of up to 200 mg/kg SGI‐1252 shows no hematological toxicity and no body weight loss in mice. Pharmacokinetic studies of SGI‐1252 in rodents also demonstrate excellent systemic exposure, with oral bioavailabilities of greater than 50% in mice and rats. Because inflammatory cytokines are known to play a role in the pathogenesis of pancreatic and lung cancers, tumor xenograft models of those cell lines were evaluated. In BxPC3 and A549 xenografts, three weeks of daily oral dosing of 200 mg/kg SGI‐1252 demonstrate exceptional activity, with tumor inhibitions of greater than 50% in both models. Pharmacodynamic studies were also performed to further elucidate the effect of SGI‐1252 on pro‐inflammatory cytokines related to these models. In several acute‐phase mouse models, where turpentine‐oil injection are utilized for cytokine stimulation, SGI‐1252 is observed to down‐regulate IL‐6 and VEGF expression 16–24 hours after dosing. In summary, SGI‐1252 is a potent oral inhibitor that is well tolerated in rodent models, provides excellent PK exposure, and demonstrates tumor growth inhibition as well as modulation of pro‐inflammatory cytokines. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C206." @default.
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- W2079803213 date "2009-12-10" @default.
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- W2079803213 title "Abstract C206:In vivoactivity of SGI‐1252, a potent, small‐molecule dual inhibitor of JAK2 and ALK2" @default.
- W2079803213 doi "https://doi.org/10.1158/1535-7163.targ-09-c206" @default.
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