Cerdulatinib 是一种选择性Tyk2抑制剂，IC50为 0.5 nM。它是JAK和Syk的双抑制剂，抑制JAK1、2、3 和Syk的IC50分别为12、6、8 和 32。

Cerdulatinib is an novel oral dual Syk/JAK inhibitor.

Cerdulatinib exhibits an inhibitory effect on 60 CLL with IC50 ranging from 0.37 to 10.02 μM. Cerdulatinib induces apoptosis in CLL in association with MCL-1 down-regulation and PARP cleavage. Cerdulatinib (2 μM) is able to overcome the support of the microenvironment and induces cell death of CLL. Cerdulatinib (250-500 nM) blocks proliferation of ibrutinib-sensitive and ibrutinib-resistant primary CLL cells. Cerdulatinib also blocks proliferation of both ibrutinib-sensitive and ibrutinib-resistant primary CLL cells as well as BTKC481S-transfected cell lines, and blocks BCR and JAK-STAT signaling pathways. Furthermore, inhibition of SYK and JAK by cerdulatinib translates to downstream inhibition of AKT and ERK. Cerdulatinib inhibits the activity of NF-kB pathway[1]. PRT062070 reduces the ability of stimulated B cells to upregulate cell-surface expression of the early activation marker CD69 (IC50=0.11 μM). PRT062070 exhibits differential potency against cytokine JAK/STAT signaling pathways. PRT062070 (1 or 3 μM) induces apoptosis in BCR-signaling competent NHL cell lines[2]. Cerdulatinib demonstrates inhibitory activity against both ABC and GCB subtypes of DLBCL cells. Cerdulatinib also induces apoptosis in both GCB and ABC subtypes of DLBCL cell lines via caspase 3 and PARP cleavage. And cerdulatinib blocks cell cycle in both ABC and GCB subtypes of DLBCL via inhibition of RB phosphorylation and down-regulation of cyclin E. Cerdulatinib induces cell cycle arrest and apoptosis under the condition of BCR stimulation in all DLBCL cell lines. Besides, cerdulatinib blocks JAK/STAT and BCR signaling in both ABC and GCB DLBCL cell lines. Cerdulatinib induces cell death in primary human DLBCL samples[3]. Cerdulatinib inhibits BCR-induced signals in a dose-dependent manner and most strongly between 0.3 to 1 μM. and particularly in IGHV-unmutated samples with greater BCR signaling capacity and response to IL4, or samples expressing higher levels of sIgM, CD49d+, or ZAP70+. Cerdulatinib overcomes anti-IgM, IL4/CD40L, or NLC-mediated protection by preventing upregulation of MCL-1 and BCL-XL; however, BCL-2 expression is unaffected. Moreover, cerdulatinib synergizes with venetoclax in vitro to induce greater apoptosis than either drug alone in samples treated with IL4/CD40L[4].

PRT062070 (0.5 mg/kg) causes a nonstatistically significant trend toward reduced ankle inflammation, whereas significant reductions in inflammation are achieved with the 1.5, 3, and 5 mg/kg doses. Besides, PRT062070 also affects anticollagen antibody formation. PRT062070 (15 mg/kg) suppresses upregulation of splenic B-cell surface CD80/86 and CD69, and inhibits BCR signaling and activation in the spleen after oral dosing in mice[2].

Cerdulatinib is dissolved in DMSO. TMD8 cells are transfected with constructs of WT BTK or BTKC481S mutants using kit V, Program U-13 on Amaxa Nucleofector. After transfection, the cells are co-cultured with NKTert cells in a 24-well plate for 24 hrs for recovery. Ibrutinib, cerdulatinib and vehicle (DMSO) are then added into the transfected TMD8 cells and cellular viability is determined with MuseTM Count & Viability kit using Muse Cell Analyzer. The cell survival is determined by flow cytometry using the Annexin V/7-AAD Apoptosis Detection Kit I on freshly isolated CLL cells.

1198300-79-6

C20H27N7O3S

445.54

PRT2070;PRT062070;赛度替尼

DMSO:~20 mg/mL (44.9 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years