Structure activity optimization of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazines as Jak1 kinase inhibitors

Friedman, Michael; Frank, Kristine E.; Aguirre, Ana L.; Argiriadi, M.A.; Davis, Heather; Edmunds, Jeremy J.; George, Dawn; George, Jonathan S.; Goedken, Eric R.; Fiamengo, Bryan A.; Hyland, Deborah; Li, Bin; Murtaza, Anwar; Morytko, Michael; Somal, Gagandeep; Stewart, Kent D.; Tarcsa, Edit; Epps, Stacy Van; Voss, Jeffrey W.; Wang, Lu; Woller, Kevin R.; Wishart, Neil

doi:10.1016/j.bmcl.2015.09.020

Cited by 16 publications

(12 citation statements)

References 18 publications

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“…We developed structural hypotheses for obtaining JAK1 selectivity using internal and external JAK protein crystal structures as described previously [14]. When examining the amino acid homology/identity in the JAK family adenosine triphosphate (ATP) binding site, sequence conservation was high.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, to achieve isoform selectivity, the design strategy focused on regions of structural differences in the active site as opposed to specific interactions with unique active site residues. Specifically, we hypothesized that the canonical glycine-rich loop assumed a “closed” backbone conformation in JAK1, in contrast to JAK2, due to amino acid sequence differences in the loop [14]. A primary design focus was to find an optimal group under the glycine-rich loop to exploit the differences in protein conformation between JAK1 and JAK2.…”

Section: Resultsmentioning

confidence: 99%

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In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494)

et al. 2018

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Background Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia. Upadacitinib (ABT-494) is a selective JAK1 inhibitor that was engineered to address the hypothesis that greater JAK1 selectivity over other JAK family members will translate into a more favorable benefit:risk profile. Upadacitinib selectively targets JAK1 dependent disease drivers such as IL-6 and IFNγ, while reducing effects on reticulocytes and natural killer (NK) cells, which potentially contributed to the tolerability issues of tofacitinib. Methods Structure-based hypotheses were used to design the JAK1 selective inhibitor upadacitinib. JAK family selectivity was defined with in vitro assays including biochemical assessments, engineered cell lines, and cytokine stimulation. In vivo selectivity was defined by the efficacy of upadacitinib and tofacitinib in a rat adjuvant induced arthritis model, activity on reticulocyte deployment, and effect on circulating NK cells. The translation of the preclinical JAK1 selectivity was assessed in healthy volunteers using ex vivo stimulation with JAK-dependent cytokines. Results Here, we show the structural basis for the JAK1 selectivity of upadacitinib, along with the in vitro JAK family selectivity profile and subsequent in vivo physiological consequences. Upadacitinib is ~ 60 fold selective for JAK1 over JAK2, and > 100 fold selective over JAK3 in cellular assays. While both upadacitinib and tofacitinib demonstrated efficacy in a rat model of arthritis, the increased selectivity of upadacitinib for JAK1 resulted in a reduced effect on reticulocyte deployment and NK cell depletion relative to efficacy. Ex vivo pharmacodynamic data obtained from Phase I healthy volunteers confirmed the JAK1 selectivity of upadactinib in a clinical setting. Conclusions The data presented here highlight the JAK1 selectivity of upadacinitinib and supports its use as an effective therapy for the treatment of RA with the potential for an improved benefit:risk profile. Electronic supplementary material The online version of this article (10.1186/s41927-018-0031-x) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494)

et al. 2018

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“…However, in RA, neither of these regulators is involved. Continuous activation of JAK/STAT signaling in synovial joints in RA leads to an increase in the expression level of the matrix metalloproteinase gene, frequency of apoptotic chondrocytes, and resistance to apoptosis in the inflamed synovial tissue [10].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Symptoms of RA, including pain, are mediated by inflammatory and non-inflammatory mechanisms and negatively affect quality of life [10]. Recently published data from a Phase III clinical trial (RA-BEAM; NCT01710358) showed that RA patients treated with JAK1 and JAK2 inhibitors achieved significantly higher pain relief than patients treated with a tumor necrosis factor blocker [10]. Stronger pain relief upon inhibition of JAK1 and JAK2 may reflect the effect on several cytokines involved in the regulation of pain in RA, as opposed to the effect on a single cytokine in the case of TNF blocking [10].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Modeling Insights into Upadacitinib Selectivity upon Binding to JAK Protein Family

et al. 2021

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Rheumatoid arthritis (RA) is a chronic disease characterized by bone joint damage and incapacitation. The mechanism underlying RA pathogenesis is autoimmunity in the connective tissue. Cytokines play an important role in the human immune system for signal transduction and in the development of inflammatory responses. Janus kinases (JAK) participate in the JAK/STAT pathway, which mediates cytokine effects, in particular interleukin 6 and IFNγ. The discovery of small molecule inhibitors of the JAK protein family has led to a revolution in RA therapy. The novel JAK inhibitor upadacitinib (RinvoqTM) has a higher selectivity for JAK1 compared to JAK2 and JAK3 in vivo. Currently, details on the molecular recognition of JAK1 by upadacitinib are not available. We found that characteristics of hydrogen bond formation with the glycine loop and hinge in JAKs define the selectivity. Our molecular modeling study could provide insight into the drug action mechanism and pharmacophore model differences in JAK isoforms.

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JAK Family Inhibitors for Autoimmune Diseases

Borzilleri

Hart

Moslin

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The JAK family of non‐receptor tyrosine kinases mediates the signaling of proinflammatory cytokines that contribute to the pathogenesis of numerous autoimmune diseases. While cytokine‐directed therapies are available to treat immune‐driven diseases, oral small‐molecule inhibitors of the JAK family (Jakinibs) have been approved as viable alternatives for the treatment of RA, PsA, and IBD. These first‐generation pan‐JAK inhibitors target the highly conserved catalytically active kinase domains in a reversible, ATP‐competitive manner, albeit in a nonselective fashion. Novel approaches to target alternative binding modes through, for example irreversible or allosteric kinase inhibition, have led to the identification of the next generation of agents, which demonstrate improved JAK family selectivity. This improved selectivity offers the potential for greater and perhaps broader efficacy by allowing for higher dosing, while avoiding undesired side effects. This article provides an overview of the JAK‐STAT signaling pathway and outlines the challenges associated with the discovery of selective JAK inhibitors while highlighting a unique allosteric TYK2 inhibitor. For each of the agents discussed, a synopsis of the medicinal chemistry efforts leading to a particular molecule is provided along with a brief summary of available preclinical and clinical efficacy and safety data.

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Structure activity optimization of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazines as Jak1 kinase inhibitors

Cited by 16 publications

References 18 publications

In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494)

In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494)

Molecular Modeling Insights into Upadacitinib Selectivity upon Binding to JAK Protein Family

JAK Family Inhibitors for Autoimmune Diseases

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