CEP-33779 / Teva - LARVOL DELTA

Selective JAK Inhibition Ameliorates Aire Deficiency–Driven Autoimmunity (CIS 2025) - "Aire KO mice underwent treatment with three selective JAK inhibitors: JAK1i (itacitinib), JAK2i (CEP-33779), and JAK3i (ritlecitinib). We show that JAK1- and JAK2-selective inhibition led to a similarly effective amelioration of IFNg-driven inflammation and tissue injury compared with the JAK1/2 inhibitor, ruxolitinib, in Aire KO mice. By contrast, although JAK3 inhibition markedly decreased lymphocytic accumulation in Aire KO mice, it appeared less effective in reducing IFNg-driven inflammation and tissue injury compared with all other tested JAK inhibitors. Our study sheds light on the differential roles of JAK inhibitors in the context of APECED-associated autoimmunity and informs future work that may help develop more selective JAK inhibitor-based treatments in APECED patients with the goal to achieve maximal efficacy and long-term safety."

Candidiasis • Immunology • Inflammation • AIRE • CD4 • CD8 • CXCL9 • IFNG • JAK3

Repression of JAK2-STAT1 and PD-L1 by CEP-33779 ameliorates the LPS-induced decline in phagocytic activity of alveolar macrophages and mitigates lung injury in mice. (PubMed, Front Immunol) - "Collectively, these findings imply that the JAK2-STAT1 pathway plays a role in the upregulation of PD-L1, which in turn is associated with the diminished phagocytic activity in LPS-induced AMs as well as lung injury. Furthermore, our study highlights that CEP-33779 treatment can effectively improve the reduced phagocytic activity of AMs and relieve lung injury induced by LPS through suppression of the JAK2-STAT1/PD-L1 pathway."

IO biomarker • Journal • Preclinical • Acute Lung Injury • Inflammation • Respiratory Diseases • IL6 • JAK2 • PD-L1 • STAT1 • TNFA

JAK2 inhibitors improve RA combined with pulmonary fibrosis in rats by downregulating SMAD3 phosphorylation. (PubMed, Int J Rheum Dis) - "JAK2 inhibitors may be an important and novel immunotherapeutic drug that can improve RA symptoms while also delaying or blocking the development of associated pulmonary fibrotic disease. The mechanism may be related to the downregulation of p-STAT3 protein via inhibition of the JAK2/STAT signaling pathway, which affects the phosphorylation of SMAD3."

IO biomarker • Journal • Preclinical • Fibrosis • Immunology • Inflammation • Inflammatory Arthritis • Interstitial Lung Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • IL1B • IL6 • SMAD3 • STAT3 • TGFB1

Comparative assessment of selective Janus Kinase inhibitors in rheumatoid arthritis mouse model: Insights into immune modulation and therapeutic implications (IMMUNOLOGY 2024) - "To better understand the roles of distinct JAK isoforms in the pathogenesis and progression of RA, we employed the Collagen-Induced Arthritis (CIA) mouse model to evaluate the effects of four selective JAK inhibitors: Upadacitinib (JAK1 inhibitor), CEP-33779 (JAK2 inhibitor), Ritlecitinib (JAK3 inhibitor), and Deucravacitinib (TYK2 inhibitor).All four JAK inhibitors showed varying degrees of alleviation in paw swelling and histological severity. We utilized flow cytometry to characterize the lymphoid and myeloid compartments within the spleen and Olink technology to analyze cytokines in the plasma.Our findings suggested that JAK1 and JAK3 play an important role in the differentiation and proliferation of T cells, while JAK2 is crucial in the development of myeloid cells. Notably, the TYK2 inhibitor exhibited significant effect in suppressing the expression of inflammatory cytokines.In summary, this study represents a comprehensive comparison of four selective JAKi in the..."

Preclinical • Immune Modulation • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • JAK3 • TYK2

Janus kinase inhibitor increases hair growth by increasing beta-catenin activity in outer root sheath cells (ISID 2023) - "Recently, JAK inhibitors have been used to treat patients with severe AA who do not respond to conventional treatments such as glucocorticosteroids, cyclosporine, and diphenylcyclopropenone...Next, we used each selective JAK inhibitor, itacitinib, CEP-33779, and ritlecitinib, to examine which JAK inhibitor regulates β-catenin...Moreover, itacitinib and CEP-33779 increased transcriptional activation of β-catenin in ORS cells in a dose-dependent manner. Therefore, this study shows that JAK1 and JAK2 inhibitors increase β-catenin activity and decrease DKK1 levels, thereby providing an additional therapeutic mechanism of JAK inhibitors other than inhibiting the JAK-STAT pathway and gives more information to dermatologists to use JAK inhibitors in patients with severe AA."

Alopecia • Dermatology • DKK1 • IFNG

JAK2 Inhibitor, Fedratinib, Inhibits P-gp Activity and Co-Treatment Induces Cytotoxicity in Antimitotic Drug-Treated P-gp Overexpressing Resistant KBV20C Cancer Cells. (PubMed, Int J Mol Sci) - "We found that co-treatment with fedratinib at low doses induced cytotoxicity in KBV20C cells treated with vincristine (VIC)...Similar to VIC, fedratinib co-treatment with other antimitotic drugs (i.e., eribulin, vinorelbine, and vinblastine) showed increased cytotoxicity in KBV20C cells. Furthermore, VIC-fedratinib had similar cytotoxic effects to co-treatment with other JAK2 inhibitors (i.e., VIC-CEP-33779 or VIC-NVP-BSK805) at the same dose; similar cytotoxic mechanisms (i.e., early apoptosis) were observed between treatments, suggesting that co-treatment with JAK2 inhibitors is generally cytotoxic to P-gp-overexpressing resistant cancer cells. Given that fedratinib is FDA-approved, our findings support its application in the co-treatment of P-gp-overexpressing cancer patients showing MDR."

Journal • Oncology • ANXA5 • CDKN1A

Canonical and noncanonical regulatory roles for JAK2 in the pathogenesis of rheumatoid arthritis-associated interstitial lung disease and idiopathic pulmonary fibrosis. (PubMed, FASEB J) - "This regulatory role of JAK2 in the pathogenesis of pulmonary fibrosis was further demonstrated by the attenuation of bleomycin-induced murine pulmonary fibrosis using a JAK2-selective pharmacological inhibitor CEP33779. In vitro studies with normal and IPF derived lung fibroblasts revealed a central role for JAK2 as an essential intermediary molecule in TGF-β-mediated myofibroblast trans-differentiation, proliferation, and extracellular matrix protein production. These observations support a crucial role for JAK2 as an intermediary molecule in fibrotic lung disease development."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease • Inflammatory Arthritis • Interstitial Lung Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • JAK2 • STAT5 • TGFB1

Co-treatment of Low Dose Pacritinib, a Phase III Jak2 Inhibitor, Greatly Increases Apoptosis of P-gp Over-expressing Cancer Cells With Multidrug Resistance. (PubMed, Anticancer Res) - "Collectively, pacritinib, induced G arrest, reduced cell viability, had high P-gp inhibitory activity, and upregulated the expression of pH2AX when used in combination with VIC. As pacritinib is a Jak2 inhibitor currently in phase III clinical trials, our findings may facilitate the application of this co-treatment in patients with MDR cancer."

Journal • P3 data • Oncology • ANXA5

EPO promotes axonal sprouting via upregulating GDF10. (PubMed, Neurosci Lett) - "Furthermore, the addition of Janus kinase 2 (JAK2) inhibitor CEP-33779 or phosphoinositide 3-kinase (PI3K) inhibitor LY294002 to the culture medium also blocked the nuclear translocation of p-p65, the expression of GDF10, and axonal sprouting, suggesting that EPO induces axonal sprouting via activating cellular JAK2 and PI3K signaling. Impeding JAK2 signaling with CEP-33779 can suppress the phosphorylation of PI3K, and this confirms that the upstream of PI3K signaling is JAK2. These present results provide a novel insight into the role of EPO and the molecular mechanism of axonal sprouting, which is beneficial for the development of novel approaches for neurological recovery after brain injury, including stroke."

Journal • Cardiovascular • CNS Disorders • Vascular Neurology

Genomic signatures defining responsiveness to allopurinol and combination therapy for lung cancer identified by systems therapeutics analyses. (PubMed, Mol Oncol) - "Treatment of resistant cell lines with allopurinol and CEP-33779 (a JAK2 inhibitor) resulted in cell death. Patient-derived tumors showed the predicted drug sensitivity in vivo. These data indicate that we can use integrated molecular information from cancer databases to predict drug responsiveness in individual patients and thus enable precision medicine."

Combination therapy • Journal

Selectively targeting JAK1 or JAK3 pathway is sufficient to reverse alopecia areata (SID 2019) - "...We found that therapeutic targeting of JAK/STAT pathways using first-generation JAK1/2 inhibitor (ruxolitinib) or pan-JAK inhibitor (tofacitinib) were effective in the treatment of human AA and in the C3H/HeJ mouse model. To further understand the role of individual JAK in AA and to produce the desired anti-inflammatory effects without unnecessary inhibition of other JAK pathways, we used JAK-selective inhibitors (JAK1-selective inhibitor Itacitinib, JAK2-selective inhibitor CEP33779 and JAK3-selective inhibitor PF06651600) to treat C3H/HeJ mice with AA...JAK1 and JAK3 inhibitors (but not JAK2 inhibitors or controls) exhibited normalized gene expression patterns similar to unaffected C3H/HeJ mice, indicating JAK1 and JAK3 inhibition suppressed the dermal inflammatory/ cytotoxic T cell signature for AA reversal. Our results contribute to a more refined understanding of JAK1 or JAK3 inhibition as a therapeutic target in AA treatment, and suggest that inhibition of JAK2..."