Janus kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. unexpectedly, the members of the type I and type II cytokine receptor families possess no catalytic kinase activity. The receptors exist as paired polypeptides, thus exhibiting two intracellular signal-transducing domains. JAKs associate with a proline-rich region in each intracellular domain, which is adjacent to the cell membrane and called a box1/box2 region. After the receptor associates with its respective cytokine/ligand, it goes through a conformational change, bringing the two JAKs close enough to phosphorylate each other.
Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family. The distinguishing feature between JAK2 and other JAK kinases is the lack of Src homology binding domains (SH2/SH3) and the presence of up to seven JAK homology domains (JH1-JH7). Loss of Jak2 is lethal by embryonic day 12 in mice. Moreover, mutations in JAK2 have been implicated in polycythemia vera, essential thrombocythemia, and myelofibrosis as well as other myeloproliferative disorders. This mutation (V617F), a change of valine to phenylalanine at the 617 position, appears to render hematopoietic cells more sensitive to growth factors such as erythropoietin and thrombopoietin.
Pacritinib (SB1518) is a potent JAK2 and FLT3 inhibitor
Myelofibrosis can present with symptomatic splenomegaly and/or cytopenias including thrombocytopenia. Actually, combined JAK1/2 inhibitory activity could potentiate thrombocytopenia. Pacritinib (SB1518), an anti-cancer agent, is a potent inhibitor of both wild-type JAK2 and JAK2V617F mutant. Besides, Pacritinib can also inhibit FLT3 and its mutant FLT3D835Y. Therefore, Pacritinib is effective in myelofibrosis and myeloproliferative neoplasm. What’s more, Pacritinib inhibits MV4-11 and MOLM-13 cells (human acute myeloid leukemias driven by an FLT3 ITD mutation). Meanwhile, Pacritinib significantly ameliorates splenomegaly and hepatomegaly in the Ba/F3-JAK2V617F engraftment model. What’s more, Pacritinib exhibits well tolerence without significant weight loss or any hematological toxicities, including thrombocytopenia and anemia.
All in all, Pacritinib is a potent inhibitor of both JAK2 and FLT3 for myelofibrosis research.
References:
[1] Levine RL, et, al. Nat Rev Cancer. 2007 Sep;7(9):673-83.
[2] Venugopal S, et, al. Blood Adv. 2022 Aug 23;6(16):4905-4913.