In vitro and in vivo characterization of SGI-1252, a small molecule inhibitor of JAK2

Department of Medicine, Division of Hematology and Bone Marrow Transplant, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Experimental hematology (Impact Factor: 2.48). 10/2010; 39(1):14-25. DOI: 10.1016/j.exphem.2010.09.013
Source: PubMed


Constitutive activation of the Janus kinase 2 (JAK2) due to a somatic mutation (JAK2(V617F)) arising in hematopoietic stem cells plays a central role in the pathophysiology of myeloproliferative neoplasms (MPNs). To investigate the hypothesis that drugs that inhibit JAK2 have therapeutic potential, we developed a small molecule inhibitor, SGI-1252, that targets the adenosine triphosphate-binding and solvent pocket of the protein.
Established cells lines each expressing different JAK2(V617F) copy numbers, a cell line transfected with wild-type and mutant JAK2, ex vivo expanded erythroid progenitor cells from patients with MPNs, and a murine xenograft model were used to characterize the activity of SGI-1252.
In vitro studies showed that SGI-1252 potently inhibits the kinase activity of wild-type JAK2, JAK2(V617F) and JAK1, but not JAK3. SGI-1252 blocked phosphorylation of signal transducers and activators of transcription 5, a downstream target of JAK2 and inhibited expression of the JAK2-dependent antiapoptotic gene BCL-X(L). Additional studies confirmed induction of apoptosis in JAK2(V617F)-positive cell lines by SGI-1252. Moreover, cell lines transfected with either wild-type JAK2 or JAK2(V617F) were equally susceptible to the antiproliferative effects of SGI-1252 and the antiproliferative activity of SGI-1252 toward ex vivo--expanded erythroid progenitors from patients with polycythemia vera and primary myelofibrosis appeared independent of the JAK2(V617F) allele burden. Pharmacodynamic studies in a murine xenograft model demonstrated both anti-tumor activity and inhibition of signal transducers and activators of transcription 5 phosphorylation by SGI-1252, and the drug was active and well-tolerated whether delivered intraperitoneally or orally.
Together, these studies support further development of SGI-1252 for clinical use.

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    • "Presence of the JAK2V617F mutation is therefore a new diagnostic marker for myeloproliferative neoplasms (MPNs) as polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Detection of this mutation has also led to the development of selective Jak2 inhibitors that might be used in near future for the treatment of these hematological diseases [6] [7] [8] [9]. JAK2V617F mutation can be detected in several different ways, each has specific advantages and limitations [10]. "
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