Preclinical characterization of itacitinib (INCB039110), a novel selective inhibitor of JAK1, for the treatment of inflammatory diseases

Covington, Maryanne; He, Xin; Scuron, Monika; Li, Jun; Collins, Robert J.; Juvekar, Ashish; Shin, Niu; Favata, Margaret; Gallagher, Karen; Sarah, Sarala; Xue, Chu‐Biao; Peel, Michael T.; Burke, Krista; Oliver, Jean; Fay, Brittany; Yao, Wenqing; Huang, Taiyi; Scherle, Peggy; Diamond, Sharon; Newton, Robert; Zhang, Yan; Smith, Paul A.

doi:10.1016/j.ejphar.2020.173505

Cited by 32 publications

(33 citation statements)

References 65 publications

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“…Itacitinib, a novel oral JAK1 selective inhibitor, exerts anti-inflammatory effects by inhibiting IL-6-driven phosphorylation STAT3. 85 A Phase I clinical trial of itacitinib in combination with pembrolizumab in patients with CRC has been conducted (NCT02646748) and was expected to end on September 31, 2020, but no results have been released yet.…”

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confidence: 99%

<p>Progress in Understanding the IL-6/STAT3 Pathway in Colorectal Cancer</p>

Lin¹,

He²,

Ye³

et al. 2020

OTT

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As a pleiotropic cytokine, interleukin-6 (IL-6) not only regulates the cellular immune response, but it also promotes tumor development by activating multiple carcinogenic pathways. IL-6 expression is significantly elevated in colorectal cancer (CRC) and is closely related to CRC development and patient prognosis. In CRC, IL-6 activates signal transducers and activators of transduction-3 (STAT3) to promote tumor initiation and tumor growth. IL-6/STAT3 signalling has a profound effect on tumor-infiltrating immune cells in the tumor immune microenvironment in CRC. Additionally, IL-6/STAT3 pathway activates downstream target genes to protect tumor cells from apoptosis; drive tumor cell proliferation, cell cycle progression, invasion and metastasis; promote tumor angiogenesis; and stimulate drug resistance. Therefore, a thorough understanding of the many effects of the IL-6/STAT3 pathway in CRC is needed, which the present review examines.

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confidence: 99%

<p>Progress in Understanding the IL-6/STAT3 Pathway in Colorectal Cancer</p>

Lin¹,

He²,

Ye³

et al. 2020

OTT

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“…Itacitinib (INCB039110) is a potent JAK1-specific inhibitor with pronounced anti-inflammatory activity in preclinical disease models. It is currently undergoing clinical trials for treatment of autoimmune/inflammatory diseases and cancers [ 207 , 224 ]. Clinical trials in hematological malignancies are summarized in Table 2 .…”

Section: The Effects Of Jakinibs On the Immune System: Focus On Cytotoxic Lymphocytesmentioning

confidence: 99%

“…Clinical trials in hematological malignancies are summarized in Table 2 . In contrast to first generation pan-/multiple-JAK inhibitors, this JAK1-specific inhibitor holds the promise of dampening inflammation driven by JAK1-dependent cytokines (like IFN-γ, IL-6), while having reduced side effects [ 207 , 224 , 225 , 226 ]. Itacitinib efficiently inhibits IL-2-induced phosphorylation of STAT3 and STAT5 and thereby IL-2-mediated T-cell proliferation.…”

Section: The Effects Of Jakinibs On the Immune System: Focus On Cytotoxic Lymphocytesmentioning

confidence: 99%

“…Itacitinib efficiently inhibits IL-2-induced phosphorylation of STAT3 and STAT5 and thereby IL-2-mediated T-cell proliferation. It suppresses pro-inflammatory cytokine signaling, including IL-6 signaling, and IL-17 production by T cells upon IL-23 stimulation [ 224 ]. These anti-inflammatory and immunosuppressive effects were confirmed in vivo in rodent models of experimentally induced arthritis, inflammatory bowel disease and alloreactive inflammatory acute GvHD [ 224 , 227 ].…”

Section: The Effects Of Jakinibs On the Immune System: Focus On Cytotoxic Lymphocytesmentioning

confidence: 99%

“…It suppresses pro-inflammatory cytokine signaling, including IL-6 signaling, and IL-17 production by T cells upon IL-23 stimulation [ 224 ]. These anti-inflammatory and immunosuppressive effects were confirmed in vivo in rodent models of experimentally induced arthritis, inflammatory bowel disease and alloreactive inflammatory acute GvHD [ 224 , 227 ]. In an MHC-mismatched mouse model of acute GvHD, Itacitinib treatment reduced inflammatory cytokine levels (including IFN-γ, TNF-α, IL-6, IL-13, and IL-1β) and T-cell numbers in the inflamed colon tissue.…”

Section: The Effects Of Jakinibs On the Immune System: Focus On Cytotoxic Lymphocytesmentioning

confidence: 99%

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Untwining Anti-Tumor and Immunosuppressive Effects of JAK Inhibitors—A Strategy for Hematological Malignancies?

Klein

Stoiber

Sexl

et al. 2021

Cancers

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The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway propagates signals from a variety of cytokines, contributing to cellular responses in health and disease. Gain of function mutations in JAKs or STATs are associated with malignancies, with JAK2V617F being the main driver mutation in myeloproliferative neoplasms (MPN). Therefore, inhibition of this pathway is an attractive therapeutic strategy for different types of cancer. Numerous JAK inhibitors (JAKinibs) have entered clinical trials, including the JAK1/2 inhibitor Ruxolitinib approved for the treatment of MPN. Importantly, loss of function mutations in JAK-STAT members are a cause of immune suppression or deficiencies. MPN patients undergoing Ruxolitinib treatment are more susceptible to infections and secondary malignancies. This highlights the suppressive effects of JAKinibs on immune responses, which renders them successful in the treatment of autoimmune diseases but potentially detrimental for cancer patients. Here, we review the current knowledge on the effects of JAKinibs on immune cells in the context of hematological malignancies. Furthermore, we discuss the potential use of JAKinibs for the treatment of diseases in which lymphocytes are the source of malignancies. In summary, this review underlines the necessity of a robust immune profiling to provide the best benefit for JAKinib-treated patients.

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Multiomics Analysis Identifies SOCS1 as Restraining T Cell Activation and Preventing Graft‐Versus‐Host Disease

Guo

Wang

et al. 2022

Advanced Science

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Graft-versus-host disease (GVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Inflammatory signaling pathways promote T-cell activation and are involved in the pathogenesis of GVHD. Suppressor of cytokine signaling 1 (SOCS1) is a critical negative regulator for several inflammatory cytokines. However, its regulatory role in T-cell activation and GVHD has not been elucidated. Multiomics analysis of the transcriptome and chromatin structure of granulocyte-colony-stimulating-factor (G-CSF)-administered hyporesponsive T cells from healthy donors reveal that G-CSF upregulates SOCS1 by reorganizing the chromatin structure around the SOCS1 locus. Parallel in vitro and in vivo analyses demonstrate that SOCS1 is critical for restraining T cell activation. Loss of Socs1 in T cells exacerbates GVHD pathogenesis and diminishes the protective role of G-CSF in GVHD mouse models. Further analysis shows that SOCS1 inhibits T cell activation not only by inhibiting the colony-stimulating-factor 3 receptor (CSF3R)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, but also by restraining activation of the inflammasome signaling pathway. Moreover, high expression of SOCS1 in T cells from patients correlates with low acute GVHD occurrence after HSCT. Overall, these findings identify that SOCS1 is critical for inhibiting T cell activation and represents a potential target for the attenuation of GVHD.

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Preclinical characterization of itacitinib (INCB039110), a novel selective inhibitor of JAK1, for the treatment of inflammatory diseases

Cited by 32 publications

References 65 publications

<p>Progress in Understanding the IL-6/STAT3 Pathway in Colorectal Cancer</p>

<p>Progress in Understanding the IL-6/STAT3 Pathway in Colorectal Cancer</p>

Untwining Anti-Tumor and Immunosuppressive Effects of JAK Inhibitors—A Strategy for Hematological Malignancies?

Multiomics Analysis Identifies SOCS1 as Restraining T Cell Activation and Preventing Graft‐Versus‐Host Disease

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