Selective Inhibition of JAK1 and JAK2 Is Efficacious in Rodent Models of Arthritis: Preclinical Characterization of INCB028050

Fridman, Jordan S.; Scherle, Peggy; Collins, Robert J.; Burn, Timothy C.; Li, Yanlong; Li, Jun; Covington, Maryanne; Thomas, Beth Ann; Collier, Paul; Favata, Margaret; Wen, Xiaoming; Shi, Jack G.; McGee, Ryan; Haley, Patrick J.; Shepard, Stacey; Rodgers, James D.; Yeleswaram, Swamy; Hollis, Greg; Newton, Robert; Metcalf, Brian W.; Friedman, Steven; Vaddi, Kris

doi:10.4049/jimmunol.0902819

Cited by 383 publications

(304 citation statements)

References 31 publications

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“…However, the formation of anti-collagen IgG was not affected in the sera of SB1578-treated mice. Thus, modulation of humoral immunity may not contribute to the observed therapeutic effects of SB1578 in the CIA model, consistent with two other reported JAK2 inhibitors (45,46).…”

Section: Discussionsupporting

confidence: 71%

“…Small-molecule inhibitors of JAKs are emerging as promising therapies for RA. Two compounds, tofacitinib (JAK1/2/3 inhibitor) and LY3009104 (JAK1/2 inhibitor), are undergoing late-stage clinical trials or nearing U.S. Food and Drug Administration approval for marketing (45,53,54). The combination of activities of SB1578 against JAK2, c-Fms, and FLT3, with selectivity for JAK2 within the JAK family, is unique.…”

Section: Discussionmentioning

confidence: 99%

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SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Madan¹,

Goh²,

Hart³

et al. 2012

The Journal of Immunology

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SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Madan¹,

Goh²,

Hart³

et al. 2012

The Journal of Immunology

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“…Together, these findings further support the observation that whole-body deletion of LITAF leads to a reduced systemic inflammatory response, providing the animals (when exposed to lethal LPS doses) greater control over the adverse effects of septic shock. Regarding local chronic inflammatory processes, we tested LITAF deficiency in CAIA (23)(24)(25). Rheumatoid arthritis is a condition emerging mainly in response to chronic overexpression of TNF-α partly regulated by LITAF.…”

Section: Discussionmentioning

confidence: 99%

Whole-body deletion of LPS-induced TNF-α factor (LITAF) markedly improves experimental endotoxic shock and inflammatory arthritis

Merrill

You

Constable

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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LPS-induced TNF-α factor (LITAF) mediates cytokine expression in response to endotoxin challenge. Previously, we reported that macrophage-specific LITAF-deficient (macLITAF −/− ) mice exposed to LPS have a delayed onset in the serum levels of proinflammatory cytokines and prolonged persistence of anti-inflammatory cytokines, but only partial protection from endotoxic shock. We postulated that greater protection might be achieved if LITAF were deleted from all LITAF-producing cells, including macrophages. Using a Cre-loxP system, we engineered a tamoxifen-induced recombination mouse [tamLITAF(i)] that resulted in whole-body LITAF deficiency. Our findings demonstrate that (i) tamLITAF(i) −/− mice are more resistant to systemic Escherichia coli LPS-induced lethality than our previous macLITAF −/− mice, providing evidence that LITAF-producing cells other than LysMCre-positive cells play an important role in mediating endotoxic shock; (ii) tamLITAF(i) −/− mice show a similar pattern of cytokine expression with decreased proinflammatory and prolonged anti-inflammatory mediators compared with WT mice; and (iii) tamLITAF(i) −/− mice, compared with WT mice, display a significant reduction in bone resorption and inflammation associated with a local chronic inflammatory disease-namely, collagen antibody-induced arthritis. Our findings offer a unique model to study the role of LITAF in systemic and chronic local inflammatory processes, and pave the way for anti-LITAF therapeutic approaches for the treatment of TNF-mediated inflammatory diseases.septic shock | multiplex

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“…TYK2 plays an important role in white blood cell function and host defenses (30,31). A number of inhibitors that target different JAKs have been approved or are in phase I-III studies for treating myelofibrosis (23,(32)(33)(34), acute myeloid leukemia (23), lymphoma (23), and rheumatoid arthritis (23,35,36). JAK inhibitors recently have been found to reprogram the SASP in senescent tumor cells, contributing to improved antitumor response (37).…”

mentioning

confidence: 99%

JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

Tchkonia

Ding

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

605

519

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Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.JAK/STAT pathway | cellular senescence | ruxolitinib | interleukin-6 | frailty

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Selective Inhibition of JAK1 and JAK2 Is Efficacious in Rodent Models of Arthritis: Preclinical Characterization of INCB028050

Cited by 383 publications

References 31 publications

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Whole-body deletion of LPS-induced TNF-α factor (LITAF) markedly improves experimental endotoxic shock and inflammatory arthritis

JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

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