Cerdulatinib (PRT2070) is an novel oral dual Syk/JAK inhibitor.

TYK2:0.5 nM, Rsk4:28 nM, MST2:15 nM, PAR1B-a:13 nM, MLK1:5 nM, GCK:18 nM, FMS:5 nM, Syk:32 nM, MST1:4 nM, AMPK:6 nM, TBK1:10 nM, TSSK:14 nM, ARK5:4 nM, JAK2:6 nM, JAK3:8 nM, JNK3:18 nM, Flt3:90 nM, JAK1:12 nM, MARK1:10 nM, ITK:194 nM, RET:105 nM, FLT4:51 nM, Chk1:42 nM, RSK2:20 nM

Cerdulatinib effectively inhibits 60 CLL cells with IC50 values ranging between 0.37 to 10.02 μM, induces apoptosis via MCL-1 down-regulation and PARP cleavage, and overcomes microenvironmental support to trigger CLL cell death at 2 μM. It inhibits both ibrutinib-sensitive and -resistant primary CLL cell proliferation at concentrations of 250-500 nM, targets BTKC481S-transfected cell lines, halts BCR and JAK-STAT signaling, and blocks SYK and JAK leading to the downstream inhibition of AKT, ERK, and the NF-kB pathway. PRT062070, with an IC50 of 0.11 μM, limits stimulated B cell activation marker CD69 expression, demonstrating varied effectiveness against JAK/STAT pathways and induces apoptosis in BCR-signaling competent NHL cell lines at 1 or 3 μM. Cerdulatinib shows inhibitory actions on both ABC and GCB DLBCL cell subtypes, induces caspase 3 and PARP cleavage-mediated apoptosis, inhibits cell cycle progression through RB phosphorylation reduction and cyclin E down-regulation, and blocks JAK/STAT and BCR signaling. It elicits cell death in DLBCL cells under BCR stimulation and in primary human DLBCL samples, disrupts BCR-induced signaling, especially potent from 0.3 to 1 μM in IGHV-unmutated, high BCR signaling, sIgM, CD49d+, or ZAP70+ expressing samples, and neutralizes anti-IgM, IL4/CD40L, or NLC-mediated protection by preventing MCL-1 and BCL-XL upregulation, without affecting BCL-2 expression. Cerdulatinib also synergizes with venetoclax to enhance apoptosis in IL4/CD40L treated samples.

Cerdulatinib (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, Cerdulatinib also affects anticollagen antibody formation. Cerdulatinib (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.

DMSO: 250 mg/mL (561.12 mM), Sonication is recommended.

10% DMSO+40% PEG300+5% Tween 80+45% Saline: 2 mg/mL (4.49 mM), Sonication is recommended.