Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia (2011)

Content Provider	CiteSeerX
Author	Kheng, B. Madan, B. Novotny-Diermayr, V. Hart, S. Tan, Yc Cheong, A. Zhou, J. Amalini, C.
Abstract	FMS-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene found in acute myeloid leukemia (AML) patients and its activating mutations have been proven to be a negative prognostic marker for clinical outcome. Pacritinib (SB1518) is a tyrosine kinase inhibitor (TKI) with equipotent activity against FLT3 (IC50 22 nM) and Janus kinase 2 (JAK2, IC50 23 nM). Pacritinib inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3 K signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Oral administration of pacritinib in murine models of FLT3-ITDdriven AML led to significant inhibition of primary tumor growth and lung metastasis. Upregulation of JAK2 in FLT3-TKIresistant AML cells was identified as a potential mechanism of resistance to selective FLT3 inhibition. This resistance could be overcome by the combined FLT3 and JAK2 activities of pacritinib in this cellular model. Our findings provide a rationale for the clinical evaluation of pacritinib in AML including patients resistant to FLT3-TKI therapy.
File Format	PDF
Publisher Date	2011-01-01
Access Restriction	Open
Subject Keyword	Combined Flt3 Clinical Evaluation Murine Model Jak2 Activity Flt3 Phosphorylation Negative Prognostic Marker Flt3-tki Therapy Flt3-internal-tandem Duplication Significant Inhibition Cellular Model Oral Administration Acute Myeloid Leukemia Flt3-itddriven Aml Flt3-wt Cell Equipotent Activity Flt3 Inhibition Fms-like Tyrosine Kinase Lung Metastasis Clinical Outcome Flt3-tkiresistant Aml Cell Primary Aml Blast Cell Primary Tumor Growth Tyrosine Kinase Inhibitor Activating Mutation Potential Mechanism Downstream Stat Jak2 Flt3 Inhibitor
Content Type	Text