SB1518: A Potent and Orally Active JAK2 Inhibitor for the Treatment of Myeloproliferative Disorders.

Abstract

JAK2 is the most common mutated gene in bcr-abl-negative chronic myeloproliferative disorders (MPDs) making it an attractive target for drug discovery. Pre-clinical studies have shown that inhibition of JAK2 signaling pathways confer therapeutic benefits in animal models of MPD. We describe here SB1518, a potent, selective and orally active inhibitor of JAK2 with therapeutic potential for the treatment of MPDs. SB1518 is a potent ATP-competitive inhibitor of both JAK2 kinase (IC50 = 22 nM) and its JAK2V617F mutant (IC50 = 19 nM) without significant activity against 40 other representative kinases across the human kinome. SB1518 selectively inhibits the proliferation of cell lines driven by JAK2 or its mutants (e.g. IC50 = 81 nM for a murine BaF3 cell line stably transfected to express erythropoietin receptor and GFP-labeled JAK2V617F). It reduces basal phosphorylation of JAK2 and STAT5 in BaF3-JAK2V617F cells in a concentration-dependent manner. The excellent physicochemical, metabolic and pharmacokinetic properties of SB1518 render it amenable to oral dosing. SB1518 was investigated in a model of advanced MPD established by intravenous injection of BaF3-JAK2V617F cells in nude mice. In several studies using different initial tumor burden and/or drug regimen, we observed dose-dependent and statistically significant therapeutic effects including normalization of elevated white blood cell count and reduction of GFP-labeled BaF3 cells in the peripheral blood, resolution of hepatosplenomegaly, reduction of phospho-STAT5 in diseased organs, prolonged survival and alleviation of terminal-stage anemia and thrombocytopenia. These therapeutic effects were observed at doses well tolerated by the animals. In conclusion, our data demonstrate the therapeutic potential of SB1518 for the treatment of myeloproliferative disorders caused by aberrant JAK2 signaling.

Profile of pacritinib and its potential in the treatment of hematologic disorders

“… 45 The structure and the pharmacological profile of pacritinib were first described by Hart et al, 45 who subsequently tested it against more than 50 other protein kinases covering all major families of the human protein kinome. 45 , 46 It was designed with the aid of computational chemistry as a small-molecule adenosine triphosphate-site competitive inhibitor of JAK2 kinase. It contains a pyrimidine core within a macrocyclic structure and has favorable physicochemical and pharmaceutical properties.…”

Experimental therapeutics for patients with myeloproliferative neoplasias

“…SB1518 is a potent and selective orally active adenosine‐5′‐triphosphate (ATP)‐competitive inhibitor of both JAK2 kinase (IC 50 = 22 nM) and the mutant JAK2 V617F (IC 50 = 19 nM) 71. It selectively inhibits the proliferation of cell lines driven by JAK2 and its mutants with an IC 50 of 81 nM for the murine Ba/F3 cell line transfected to express Epo receptor and JAK2 V617F .…”

“…SB1518 was evaluated in a murine model of MPN that was established via intravenous injection of Ba/F3‐JAK2 V617F cells. Significant therapeutic effects were observed, including normalization of leukocytosis, reduction of green fluorescent protein (GFP)‐labeled Ba/F3 cells in the peripheral blood, resolution of hepatosplenomegaly, reduction of phospho‐STAT5, alleviation of anemia and thrombocytopenia, and prolonged survival 71. A phase 1 dose escalation study of SB1518 with 6 dose levels ranging from 100 mg to 600 mg daily was given to 31 patients with MF.…”

Molecular drug targets in myeloproliferative neoplasms: mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1

“…Amongst them, some are JAK2 selective ATP‐mimetic small molecules: e.g. TG101209, TG101348, INCB018424, XL019, CEP701 and SB1518 [205–208]. TG101209, an orally available small molecule JAK2 ‐selective kinase inhibitor, is one of the first compounds to undergo extensive preclinical testing [209].…”

“…Several other potent JAK2 inhibitors have also been reported to have in vitro or in vivo (i. e. mouse models) activity against JAK2 V617F‐driven cell proliferation and signal transduction. Among them, INCB018424, XL019, CEP‐701 and SB1518 are currently undergoing clinical trials in patients with advanced stages of PMF or post‐PV/ET MF (INCB018424, XL019, CEP701), PV (XL019, CEP701), JAK2 V617F‐positive ET (CEP701) and acute and chronic haematologic malignancies (SB1518) [206–208, 213, 214]. All of these drugs display potent JAK2 inhibitory activity but their in vitro JAK2 selectivity, in the context of the JAK family of kinases, is different.…”