The JAK/STAT pathway forms a critical node affecting multiple signaling pathways in both the innate and adaptive immune responses. Janus kinase 2 (JAK2) belongs to the non-receptor tyrosine kinase family. JAK2 is widely distributed in the cytoplasm of a variety of somatic cells, involved in cell-cycle regulation, apoptosis, mitotic chromosome recombination, genetic instability, and heterochromatin changes, and other biological processes. CEP-33779 is a highly selective, small-molecule inhibitor of JAK2 with an IC50 of 1.8 nMDugan BJ, Gingrich DE, Mesaros EF, Milkiewicz KL, Curry MA, Zulli AL, Dobrzanski P, Serdikoff C, Jan M, Angeles TS, Albom MS, Mason JL, Aimone LD, Meyer SL, Huang Z, Wells-Knecht KJ, Ator MA, Ruggeri BA, Dorsey BD. A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of Janus kinase 2 for use in anticancer therapy: discovery of CEP-33779. J Med Chem. 2012 Jun 14;55(11):5243-54. doi: 10.1021/jm300248q. Epub 2012 May 18. PMID: 22594690.}https://pubmed.ncbi.nlm.nih.gov/22594690/. Administration of CEP-33779 in a therapeutic mode resulted in a reduction in colorectal tumor mass, decreased levels of proinflammatory cytokines, and inhibition of STAT3 and NF-κB activation. In addition, it caused histologic reductions in cancer grades, and a negative impact on the tumor microenvironment including reduced tumor cell proliferation and angiogenesis upon JAK2 inhibition. With advanced development, CEP-33779 can deplet the autoreactive plasma cells, treat lupus nephritis in mice, ablate disease in two different mouse models of rheumatoid arthritis and administration of CEP-33779 results in significant inhibition of tumor growth in an AOM/DSS-induced model of colorectal cancer[3]. In a vitro study, KBV20C cells were then stimulated for 72h with CEP-33779 ranging from 5-10 μM. The result showed that JAK2 inhibitor CEP-33779 increased sensitization of KBV20C cells to VIC-induced mitotic-arrest[4]. In a vivo study, using a mouse model of colitis-induced colorectal cancer, JAK2 inhibitor, CEP-33779 induced regression of established colorectal tumors, reduced angiogenesis, and reduced proliferation of tumor cells with an increasing doses of 10 mg/kg, 30 mg/kg, and 55 mg/kg[3].
CEP-33779 significantly improved the LPS-induced reduction in phagocytic activity of MH-S cells
Front Immunol. 2024 Nov 26;15:1472425.
KBV20C cells
2 µM
24 h
CEP-33779 co-treatment with VIC increased cytotoxicity in KBV20C cells, inducing early apoptosis.
Int J Mol Sci. 2022 Apr 21;23(9):4597.
NCI-H1975
1.6, 3.2, 16 µM
48 h
To evaluate the cytotoxicity of CEP-33779 in combination with allopurinol on resistant cell lines. The results showed that combination treatment significantly reduced cell viability, indicating a synergistic effect.
Mol Oncol. 2019 Aug;13(8):1725-1743.
HCC827
1.6, 3.2, 16 µM
48 h
To evaluate the cytotoxicity of CEP-33779 in combination with allopurinol on resistant cell lines. The results showed that combination treatment significantly reduced cell viability, indicating a synergistic effect.
CEP-33779 significantly mitigated LPS-induced lung injury and inflammatory response in mice
Front Immunol. 2024 Nov 26;15:1472425.
Mice
Collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models
Oral
10 mg/kg, 30 mg/kg, 55 mg/kg, 100 mg/kg
Twice daily for 4 to 8 weeks
CEP-33779 significantly reduced paw edema and clinical scores in both CIA and CAIA models, and decreased local and serum cytokine levels, indicating its potential for treating rheumatoid arthritis.
Arthritis Res Ther. 2011 Apr 21;13(2):R68
NCR-nude mice
Tumor xenograft model
Oral gavage
10 mg/kg
Three times a week for 30 days
To evaluate the inhibitory effect of CEP-33779 in combination with allopurinol on tumor growth. The results showed that combination treatment significantly reduced tumor volume, indicating a synergistic effect.
Mol Oncol. 2019 Aug;13(8):1725-1743.
C3H/HeJ mice
Alopecia areata model
Systemic administration
50 mg/kg
12 weeks
CEP-33779 failed to restore hair regrowth and did not prevent further progressive hair loss.
Inhibition of JAK2 in human TF-1 cells using GM-CSF pretreated for 1 hr prior to GM-CSF addition measured after 5 hrs by FRET based GeneBLAzer assay, IC50=0.061 μM
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