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Cerdulatinib HCl (formerly PRT2070; PRT062070) is a novel, potent, selective orally bioactive, and multi-targeted tyrosine kinase inhibitor of JAK1/2/3/TYK2 and Syk with potential antitumor activity. It inhibits JAK1/JAK2/JAK3/TYK2 and Syk with IC50s of 12 nM/6 nM/8 nM/0.5 nM and 32 nM, respectively. It shows potent in vitro antiproliferative activity and high in vivo antitumor efficacy. Cerdulatinib also inhibits 19 other tested kinases with IC50 less than 200 nM. It is currently being studied in patients with genetically-defined hematologic cancers, as well as for patients who have failed therapy due to relapse or acquired mutations.
Physicochemical Properties
| Molecular Formula | C20H28CLN7O3S |
| Molecular Weight | 482 (HCl salt) |
| Exact Mass | 481.166 |
| Elemental Analysis | C, 49.84; H, 5.86; Cl, 7.35; N, 20.34; O, 9.96; S, 6.65 |
| CAS # | 1369761-01-2 |
| Related CAS # | Cerdulatinib;1198300-79-6 |
| PubChem CID | 56960607 |
| Appearance | Typically exists as light brown to brown solids at room temperature |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 9 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 32 |
| Complexity | 711 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | Cl.S(CC)(N1CCN(C2C=CC(=CC=2)NC2=NC=C(C(N)=O)C(=N2)NC2CC2)CC1)(=O)=O |
| InChi Key | BGLPECHZZQDNCD-UHFFFAOYSA-N |
| InChi Code | 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) |
| Chemical Name | 4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide hydrochloride InChi Key: BGLPECHZZQDNCD-UHFFFAOYSA-N |
| Synonyms | PRT062070; PRT 062070; PRT062070, PRT2070; PRT2070; PRT-2070; PRT 2070; PRT-06270 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | 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 |
| ln Vitro | 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]. |
| ln Vivo | 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]. |
| Enzyme Assay | 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]. |
| Cell Assay |
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. 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 Protocol |
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. 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. |
| References |
[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. |
| Additional Infomation | 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] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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. 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. 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. Solubility in Formulation 4: 5% DMSO+corn oil: 3mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |