Janus kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. Mammals have four members of this family, JAK1, JAK2, JAK3 and Tyrosine kinase 2 (Tyk2). Birds, fish and insects also have JAKs. Since members of the type I and type II cytokine receptor families possess no catalytic kinase activity, they rely on the JAK family of tyrosine kinases to phosphorylate and activate downstream proteins involved in their signal transduction pathways. 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. The JAK autophosphorylation induces a conformational change within itself, enabling it to transduce the intracellular signal by further phosphorylating and activating transcription factors called STATs.
Spleen tyrosine kinase (Sky) is a cytosolic non-receptor protein tyrosine kinase (PTK) that exsists in hematopoietic cells (such as mast cells, B lymphocytes, T lymphocytes, neutrophils, dendritic cells, and macrophages) and in non-hematopoietic cells. Syk associates with different receptors on the surface of various cells such as B cells, mast cells, monocytes, macrophages, and neutrophils, and even osteoclasts and breast cancer cells. Following the engagement of these receptors with their ligands, Syk is activated and orchestrates diverse cellular responses. Sky has a crucial role in adaptive immune receptor signalling. However, recent reports indicate that Syk also mediates other, unexpectedly diverse biological functions, including cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development.
Cerdulatinib (PRT062070) is a reversible ATP-competitive dual JAK and Syk inhibitor.
Cerdulatinib can inhibit anti-Ig and IL-4 signalling in vitro in normal human lymphocytes and to inhibit B-cell receptor (BCR)-induced B-cell activation and splenomegaly in vivo in mice. Besides, Cerdulatinib also induces apoptosis in primary diffuse large B-cell lymphoma (DLBCL) cell lines in vitro and inhibited BCR-mediated signalling. Cerdulatinib inhibits IL-4 and BCR-mediated signalling which resulted in apoptosis, particularly in samples with markers of progressive disease, and synergised with venetoclax (ABT-199) in vitro. These data suggest that Cerdulatinib has potential for the research of chronic lymphocytic leukemia.
References:
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[3] Blunt MW, et, al. Clin Cancer Res. 2017 May 1;23(9):2313-2324.