The JAK/STAT pathway forms a critical node affecting multiple signaling pathways in both the innate and adaptive immune responses. JAK family members include Janus kinases 1, 2, and 3 (JAK1, JAK2, and JAK3, respectively) and tyrosine kinase 2 (TYK2). JAK1 and JAK2 and TYK2 are broadly activated by different cytokines across cell types, while JAK3 is limited to primarily hematopoietic cells. Cerdulatinib/PRT-062070 is an orally active nonspecific kinase inhibitor with an IC50 of 0.5, 12, 6, or 8 nM for TYK2, JAK1, JAK2, or JAK3, respectively. At the cellular level, cerdulatinib demonstrates specificity towards JAK1/JAK3 and TYK2, but not JAK2-mediated responses and it is currently in phase 1/2A clinical trials for CLL (chronic lymphocytic leukemia) as well as other B-cell Non Hodgkin lymphomas, with first in man clinical trial data and therapeutic responses in patients resistant to ibrutinib already reported. The specificity of cerdulatinib was also demonstrated by its lack of inhibition of T cell receptor signaling or protein kinase C signaling in whole blood[3]. On a tissue microarray of 62 primary DLBCL (large B-cell lymphoma) tumors with 58% expressed either phosphorylated SYK or STAT3 or both. Cerdulatinib induced DLBCL cells apoptosis which was associated with caspase-3 and PARP cleavage with IC50 of 32 nM and 12 nM for SYK and JAK1[4]. PBMCs from CLL patients were treated with cerdulatinib ranging from 0-1μM. Cerdulatinib induced apoptosis of CLL cells in a time- and concentration-dependent manner, and particularly in IGHV unmutated samples with greater BCR-signaling capacity and response to IL-4, which showed that Cerdulatinib is a promising therapeutic for the treatment of CLL either alone or in combination with venetoclax[5].
作用机制
The functional groups that interact with Leu377, Gly378, and Val385 in the G-loop and the nearby region in SYK (Spleen tyrosine kinase) can bind to the enzyme pocket.
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