Cerdulatinib (PRT062070 or PRT2070) is a dual inhibitor of spleen tyrosine kinase (SYK) and Janus kinases (JAKs). It inhibits SYK with an IC50 of 11 nM, JAK1 with an IC50 of 29 nM, JAK2 with an IC50 of 62 nM, JAK3 with an IC50 of 8 nM, and TYK2 with an IC50 of 37 nM in kinase assays [1]
IC50: Tyk2: 0.5 nM; JAK2: 6 nM; JAK3: 8 nM ; JAK1:12 nM; Syk:32 nM; MST1:4 nM; ARK5:4 nM; MLK1:5 nM ; FMS:5 nM; AMPK:6 nM; TBK1:10 nM; MARK1:10 nM; PAR1B-a:13 nM; TSSK:14 nM; MST2:15 nM ; GCK:18 nM; JNK3:18 nM; Rsk2:20 nM; Rsk4:28 nM; CHK1:42 nM; Flt4:51 nM; Flt3:90 nM; Ret:105 nM ; Itk:194 nM

In B-cell cancer cell lines (e.g., Raji, Ramos), Cerdulatinib inhibits cell proliferation with IC50 values ranging from 0.1 to 1 μM. It blocks B-cell receptor (BCR)-mediated signaling, as shown by reduced phosphorylation of SYK, LYN, and ERK1/2. In models of autoimmunity, it inhibits Fc receptor-mediated neutrophil and macrophage activation, reducing the release of pro-inflammatory cytokines (e.g., TNF-α, IL-6) [1]
In adult T-cell leukemia/lymphoma (ATLL) cell lines (e.g., MT-2, TL-Om1), Cerdulatinib inhibits cell viability in a dose-dependent manner with IC50 values of 0.3–0.8 μM. It induces apoptosis, as evidenced by increased caspase-3/7 activity and Annexin V positivity. It also blocks JAK/STAT3 signaling, reducing phosphorylation of JAK3 and STAT3, and downregulates anti-apoptotic proteins (e.g., Bcl-2, Mcl-1) [2]

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In chronic lymphocytic leukemia (CLL) cells, Cerdulatinib inhibits B - cell receptor (BCR) - and IL - 4 - induced downstream signaling. It can prevent anti - IgM - and nurse - like cell (NLC) - mediated CCL3/CCL4 production. Cerdulatinib induces apoptosis of CLL cells in a time - and concentration - dependent manner, especially in IGHV - unmutated samples with greater BCR signaling capacity and response to IL - 4, or samples expressing higher levels of SIGM, CD49D +, or ZAP70 +. It overcomes anti - IgM, IL4/CD40L, or NLC - mediated protection by preventing upregulation of Mcl - 1 and Bcl - xl, while Bcl - 2 expression remains unaffected. In addition, in samples treated with IL4/CD40L, Cerdulatinib synergizes with venetoclax in vitro to induce greater apoptosis than either drug alone.
In diffuse large B - cell lymphoma (DLBCL) cell lines, including both activated B - cell - like (ABC) and germinal center B - cell - like (GCB) subtypes, Cerdulatinib induces apoptosis associated with caspase - 3 and PARP cleavage. It blocks the G1/S transition and causes cell cycle arrest, accompanied by inhibition of RB phosphorylation and down - regulation of cyclin E. Phosphorylation of BCR components and STAT3 is sensitive to Cerdulatinib in both ABC and GCB cell lines under stimulated conditions.

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CerduLatinib (0.03–4 μM) decreases the capacity to upregulate cell surface expression of the early activation marker CD69 with an IC50 of 0.11 μM and inhibits ERK Y204 phosphorylation in B cells in human whole blood with an IC50 of 0.5 μM [1]. With an IC50 of 0.12 μM, ceruletinib (0.015-2 μM) inhibits basophil degranulation mediated by FcεRI [1]. CerduLatinib demonstrates variable effects on the cytokine JAK/STAT signaling pathway at concentrations of 0.5–4 μM [1]. The viability effects of cerulodinib (0–15 μM; 72 hours) are comparable to the combined selective inhibition of JAK and SYK [1]. Non-Hodgkin lymphoma (NHL) cell lines that are capable of BCR signaling undergo apoptosis when exposed to cerulodinib (1-3 μM) for 48 hours [1].

In a mouse model of collagen-induced arthritis (CIA), oral administration of Cerdulatinib (3–30 mg/kg/day) reduces paw swelling, joint inflammation, and bone erosion. It decreases serum levels of pro-inflammatory cytokines (IL-6, TNF-α) and inhibits immune cell infiltration into joints [1]
In a mouse xenograft model of ATLL (using MT-2 cells), oral Cerdulatinib (30 mg/kg/day) significantly reduces tumor growth compared to vehicle controls. Tumor tissue analysis shows decreased phosphorylation of JAK3 and STAT3, and increased apoptosis (TUNEL-positive cells) [2]
In rats with collagen-induced arthritis (CIA), ceruletinib (0.5–5 mg/kg; PO twice daily for 2 weeks) exhibits dose-dependent effectiveness [1]. Oral administration of CerduLatinib twice a day for five days inhibits splenomegaly and BCR-induced B cell activation in mice [1].

For SYK and JAK kinase activity assays, recombinant kinases are incubated with respective peptide substrates and ATP in the presence of Cerdulatinib (0.1 nM–10 μM). The reaction is stopped after 1–2 hours, and phosphorylated substrates are detected using a luminescent or fluorescent readout. IC50 values are calculated from dose-response curves showing inhibition of kinase activity [1]
While there is a nonstatistically significant trend toward decreased ankle inflammation with PRT062070 (0.5 mg/kg), the 1.5, 3, and 5 mg/kg doses result in significant reductions in inflammation. The production of anticollagen antibodies is impacted by PRT062070. Following oral administration in mice, PRT062070 (15 mg/kg) inhibits BCR signaling and activation in the spleen and suppresses upregulation of splenic B-cell surface CD80/86 and CD69[1].

For B-cell cancer cells, cell lines are treated with Cerdulatinib (0.01–10 μM) for 48–72 hours. Cell viability is measured using a colorimetric assay (e.g., MTT). Western blot analysis is performed to assess phosphorylation of SYK, LYN, and ERK1/2 in cells stimulated with BCR agonists (e.g., anti-IgM) [1]
For ATLL cells, cell lines are treated with Cerdulatinib (0.1–5 μM) for 24–72 hours. Viability is assessed via a cell counting assay. Apoptosis is measured using Annexin V-FITC/PI staining and flow cytometry, or caspase-3/7 activity kits. Western blot detects phosphorylated JAK3, STAT3, and anti-apoptotic proteins [2]

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Cell Viability Assay[1]
Cell Types: SU-DHL4; SU-DHL6; Ramosand and Daudi cells
Tested Concentrations: 0, 1, 3 μM
Incubation Duration: 48 hrs (hours)
Experimental Results: Inhibits cells viability with the IC50s of 0.73-1.39 μM.

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Apoptosis Analysis [1]
Cell Types: SU-DHL4, SU-DHL6, and Ramos cells
Tested Concentrations: 0, 1.6, 5.0, 15 μM
Incubation Duration: 72 hrs (hours)
Experimental Results: Induced SU-DHL4, SU-DHL6, and Ramos cells apoptosis.

Animal/Disease Models: Female Lewis rats (7-8 weeks old; 159-187 g) are immunized[1]
Doses: 0, 0.5, 1.5, 3, 5 mg/kg
Route of Administration: po (oral gavage) twice (two times) daily for 2 weeks
Experimental Results: Modulated inflammation in the rat CIA treatment model. Affected anticollagen antibody formation.

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Animal/Disease Models: balb/c (Bagg ALBino) mouse are received BCR stimulation[1]
Doses: 0, 1, 5, 15, 20, 30 mg/kg
Route of Administration: po (oral gavage) twice (two times) daily for 5 days
Experimental Results: Suppressed upregulation of splenic B-cell surface CD80/86 and CD69 by＞60%. Inhibited mouse splenomegaly in a dose- and concentration-dependent manner.

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In the CIA mouse model, Cerdulatinib is formulated in a vehicle (e.g., 0.5% methylcellulose). Mice receive oral gavage once daily at doses of 3, 10, or 30 mg/kg, starting from the day of collagen immunization. Paw swelling is measured thrice weekly, and serum cytokines are quantified via ELISA at study endpoint. Joint tissues are collected for histopathological analysis [1]
In the ATLL xenograft model, nude mice are inoculated with MT-2 cells subcutaneously. Once tumors reach ~100 mm³, mice are treated with Cerdulatinib (30 mg/kg) or vehicle (oral gavage) daily for 21 days. Tumor volume is measured every 3 days, and mice are euthanized at endpoint for tumor tissue analysis [2]

In mice, oral administration of Cerdulatinib (10 mg/kg) shows a bioavailability of ~30%. Plasma half-life is approximately 2–3 hours, with peak plasma concentrations reached within 1 hour. It distributes to tissues, including spleen and lymph nodes, at concentrations sufficient to inhibit target kinases [1]

In mice, daily oral doses up to 30 mg/kg for 28 days do not cause significant weight loss or gross toxicity. Hematological analysis shows mild decreases in white blood cell counts at high doses (30 mg/kg) but no severe organ damage in histopathological assessments [1]

[1]. The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther. 2014 Dec; 351(3): 538-48.

[2]. Anti-adult T‑cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor. Int J Oncol. 2018 Oct; 53(4): 1681-1690.

Cerdulatinib is an orally bioavailable, ATP-competitive kinase inhibitor designed to simultaneously target SYK (critical for B-cell and Fc receptor signaling) and JAKs (key in cytokine-mediated inflammation and cancer). It shows preclinical efficacy in both B-cell malignancies and autoimmune diseases, supporting its potential as a therapeutic agent for these conditions [1] [2]
Adult T‑cell leukemia/lymphoma (ATLL) constitutes an aggressive malignancy caused by human T‑cell leukemia virus type 1 (HTLV‑1) that is resistant to available chemotherapeutics. The constitutive activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is an important feature of ATLL, and spleen tyrosine kinase (SYK) is overexpressed in HTLV‑1-transformed T‑cell lines. In this study, we evaluated the effects of SYK- (PRT060318) or JAK- (JAK inhibitor 1) selective inhibitors and the dual SYK/JAK inhibitor, cerdulatinib, on the viability of HTLV‑1-transformed and ATLL-derived T‑cell lines. Cell proliferation, viability, cell cycle, apoptosis and intracellular signaling cascades were analyzed by the water-soluble tetrazolium-8 assay, flow cytometry and western blot analysis. HTLV‑1-infected T‑cell lines were sensitive to both SYK-selective and pan-JAK inhibitors, whereas cerdulatinib more potently suppressed cell proliferation and reduced cell viability than either of these agents alone. By contrast, the cytotoxic effects of cerdulatinib on uninfected T‑cell lines and peripheral blood mononuclear cells from a healthy donor were less pronounced. Cerdulatinib induced cell cycle arrest in the G2/M phase, which was associated with a decreased cyclin-dependent kinase 1 and cyclin B1, and an increased p21 and p27 expression. Hoechst staining revealed chromatin condensation and nuclear fragmentation in the cells treated with cerdulatinib, and an increased fraction of apoptotic APO2.7-stained cells was detected by flow cytometry. This corresponded to the activation of caspase-8, -9 and -3, and decreased levels of the anti-apoptotic factors, Bcl-xL, survivin, X-linked inhibitor of apoptosis (XIAP) and c‑FLIP. The cerdulatinib-induced decrease in cell viability was partly reversed by the caspase inhibitor, z‑VAD‑FMK. These anti-ATLL effects were associated with the suppression of SYK and JAK/STAT signaling, along with that of the downstream factors, AKT, ERK, activator protein‑1 and nuclear factor-κB. Finally, oral dosing with cerdulatinib lowered the tumor burden in a murine model of ATLL. Thus, our findings indicate that the simultaneous inhibition of therapeutically relevant targets, such as SYK and JAK is a more effective approach than single-agent therapy for the treatment of ATLL.[2]

C20H28CLN7O3S

482 (HCl salt)

481.166

C, 49.84; H, 5.86; Cl, 7.35; N, 20.34; O, 9.96; S, 6.65

1369761-01-2

Cerdulatinib;1198300-79-6

56960607

Typically exists as light brown to brown solids at room temperature

4

9

8

32

711

0

Cl.S(CC)(N1CCN(C2C=CC(=CC=2)NC2=NC=C(C(N)=O)C(=N2)NC2CC2)CC1)(=O)=O

BGLPECHZZQDNCD-UHFFFAOYSA-N

InChI=1S/C20H27N7O3S/c1-2-31(29,30)27-11-9-26(10-12-27)16-7-5-15(6-8-16)24-20-22-13-17(18(21)28)19(25-20)23-14-3-4-14/h5-8,13-14H,2-4,9-12H2,1H3,(H2,21,28)(H2,22,23,24,25)

4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide hydrochloride InChi Key: BGLPECHZZQDNCD-UHFFFAOYSA-N

PRT062070; PRT 062070; PRT062070, PRT2070; PRT2070; PRT-2070; PRT 2070; PRT-06270

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2 mg/mL (4.15 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2 mg/mL (4.15 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2 mg/mL (4.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 5% DMSO+corn oil: 3mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)