Cerdulatinib (PRT-062070, PRT2070) is an oral active, multi-targeted tyrosine kinase inhibitor with IC50 of 12 nM/6 nM/8 nM/0.5 nM and 32 nM for JAK1/JAK2/JAK3/TYK2 and Syk, respectively. Also inhibits 19 other tested kinases with IC50 less than 200 nM.
Targets
TYK2 [1](Cell-free assay)
MST1 [1](Cell-free assay)
ARK5 [1](Cell-free assay)
MLK1 [1](Cell-free assay)
Fms [1](Cell-free assay)
0.5 nM
4 nM
4 nM
5 nM
5 nM
In vitro
In human whole blood from normal donors, Cerdulatinib affects BCR-mediated B-cell activation by dual inhibition of SYK and JAK. As a dual SYK/JAK inhibitor, Cerdulatinib significantly reduces cell viability in a subset of NHL cell lines, and induces apoptosis in BCR-signaling competent NHL cell lines. [1]
Assay
Methods
Test Index
PMID
Western blot
Mcl-1 / PARP ;
PubMed: 28088788
Immunoblots of MCL-1 and PARP. Following cerdulatinib treatment for 48 hrs at indicated concentrations, MCL-1 and PARP1 cleavage were measured by Western blot in whole cell lysates. GAPDH was included as the loading control.
p-SYK / SYK / p-BTK / BTK ;
PubMed: 28088788
Immunoblots for early BCR components SYK and BTK following cerdulatinib treatment. Freshly isolated CLL cells (N= 6) were treated with increasing doses of cerdulatinib in the presence of combined stimulation with soluble anti-IgM, CD40L and CpG. p-SYK, total SYK, p-BTK and total BTK were blotted in whole cell extracts. GAPDH served as a loading control.
C. Immunoblots for JAK-STAT following IL4 stimulation and cerdulatinib treatment. Freshly isolated CLL cells (N= 6) were treated with increasing concentrations of cerdulatinib in the presence of combined stimulation with anti-IgM, CD40L and CpG. p-JAK1, total JAK1, p-JAK3, total JAK3, p-STAT6 and t-STAT6 were blotted in whole cell extracts. D.Immunoblots for JAK-STAT following IL6 stimulation and cerdulatinib treatment. Freshly isolated CLL cells (N= 4) were treated with increasing doses of cerdulatinib in the presence of IL-6. P-JAK1, total JAK1, p-JAK2, total JAK2, p-STAT3 and t-STAT3 were blotted in whole cell extracts.
28088788
Growth inhibition assay
Cell metabolic activity;
PubMed: 26575169
A.DLBCL cell lines were treated with various concentrations of cerdulatinib for 72 h followed by MTT assay. GCB are highlighted in blue and ABC in red.B.IC50values were calculated.
26575169
In vivo
In a rat collagen-induced arthritis model, Cerdulatinib (5 mg/kg p.o.) significantly improves inflammatory infiltrate within the synovium and the integrity of the articular cartilage. In addition, Cerdulatinib also blocks BCR-induced B-cell activation and splenomegaly in mice. [1]
