Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design

Lee, Katherine L.; Ambler, Catherine M.; Anderson, David R.; Boscoe, Brian P.; Bree, Andrea; Brodfuehrer, Joanne; Chang, Jeanne S.; Choi, Chulho; Chung, Seok Won; Curran, Kevin J.; Day, Jacqueline E.; Dehnhardt, Christoph M.; Dower, Ken; Drozda, Susan E.; Frisbie, Richard K.; Gavrin, Lori Krim; Goldberg, Joel; Han, Seungil; Hegen, Martin; Hepworth, David; Hope, Heidi R.; Kamtekar, S.; Kilty, Iain; Lee, Arthur; Lin, Lih-ling; Lovering, Frank; Lowe, Michael; Mathias, John P.; Morgan, Heidi M; Murphy, E. Angela; Παπαϊωάννου, Νικόλαος; Patny, Akshay; Pierce, Betsy S.; Rao, Vikram; Saiah, Eddine; Samardjiev, Ivan J.; Samas, Brian; Shen, Marina W.H.; Shin, Julia; Soutter, Holly H.; Strohbach, Joseph W.; Symanowicz, Peter T.; Thomason, Jennifer R.; Trzupek, John D.; Vargas, Richard; Vincent, Fabien; Yan, Jiangli; Zapf, Christoph W.; Wright, Stephen W.

doi:10.1021/acs.jmedchem.7b00231

Cited by 113 publications

(124 citation statements)

References 64 publications

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“…IRAK-4 deficiency is associated with bacterial infections in humans 35 and in mice 40 . Consistent with the involvement of the TLR signalling pathway at the crossroads between gut microbiota and dietary lipids 41,42 , IRAK-4 deletion and its inhibition by TMA and PF06650833 38 rescued HFD-induced low-grade inflammation and IR 4,43,44 , highlighting new unexpected roles for this microbial metabolite and its target kinase in immunometabolism. The relative IC 50 (3.4 μM) we determined is two times smaller than the plasma isotopic quantifications obtained by UPLC-MS/MS in the HFD group supplemented with choline.…”

Section: Discussionsupporting

confidence: 55%

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Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control

Chilloux

Brial

Everard

et al. 2018

Preprint

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Referenced abstract The interaction between high-fat diet (HFD) feeding and the gut microbiome has a strong impact on the onset of insulin resistance (IR)1-3. In particular, bacterial lipopolysaccharides (LPS) and dietary fats trigger low-grade inflammation4 through activation of Toll-like receptor 4 (TLR4), a process called metabolic endotoxemia5. However, little is known about how the microbiome can mitigate this process. Here, we investigate longitudinal physiological and metabotypical responses of C57BL/6 mice to HFD feeding. A series of in vivo experiments with choline supplementation, then blocking trimethylamine (TMA) production and administering TMA, demonstrate that this microbiome-associated metabolite decouples inflammation and IR from obesity in HFD. Through in vitro kinome screens and in silico molecular dynamics studies, we reveal TMA specifically inhibits Interleukin-1 Receptor-associated Kinase 4 (IRAK-4), a central kinase integrating signals from various TLRs and cytokine receptors. Consistent with this, genetic ablation and chemical inhibition of IRAK-4 result in similar metabolic and immune improvements in HFD. In summary, TMA appears as a key microbial effector inhibiting IRAK-4 and mediating metabolic and immune effects with benefits upon HFD. Thereby we highlight the critical contribution of the microbial signalling metabolome in homeostatic regulation of host disease and the emerging role of the kinome6 in microbial–mammalian chemical crosstalk.

show abstract

Section: Discussionsupporting

confidence: 55%

“…Since the Irak4 -/- mice lack the whole protein, we compared the knock-out phenotype with the phenotype of PF06650833, a recently discovered chemical inhibitor of the human IRAK4 protein 38 currently being assessed in a clinical trial (NCT02996500). Treatment with PF06650833 improved BW in LC-HFD mice (Suppl.…”

Section: Main Textmentioning

confidence: 99%

Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control

Chilloux

Brial

Everard

et al. 2018

Preprint

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show abstract

“…To translate our findings, we tested 2 different IRAK4 inhibitors. Of these, PF06650833 is being tested in clinical trial (35), and AS2444697 was shown to protect inflammation-associated renal failure in rats (36). We previously showed that AS2444697 blocks IL-1β-induced NF-κB activation in pancreatic cancer cells (27,36).…”

Section: Resultsmentioning

confidence: 99%

IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer

Li¹,

Chen²,

Zhang³

et al. 2019

JCI Insight

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“…To confirm that the observations in the heterologous expression system are relevant to primary cells and not due to artifacts of overexpression of the constructs, we treated primary human neonatal dermal fibroblasts with 2 ng/ml IL-1␤ and monitored phosphoprotein signaling and cytokine release in the presence of the highly selective and potent IRAK4 inhibitor PF-06650833 (compound 40 in Lee et al (18)). A concentration of 200 nM PF-06650833, which completely suppresses IRAK4 autophosphorylation (see Fig.…”

Section: Inhibition Of Irak4 In Primary Human Dermal Fibroblasts Usinmentioning

confidence: 96%

Mechanism of dysfunction of human variants of the IRAK4 kinase and a role for its kinase activity in interleukin-1 receptor signaling

Karim

Kiessu

et al. 2018

Journal of Biological Chemistry

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Interleukin-1 receptor (IL1R)-associated kinase 4 (IRAK4) is a central regulator of innate immune signaling, controlling IL1R and Toll-like receptor (TLR)-mediated responses and containing both scaffolding and kinase activities. Humans deficient in IRAK4 activity have autosomal recessive primary immune deficiency (PID). Here, we characterized the molecular mechanism of dysfunction of two IRAK4 PID variants, G298D and the compound variant R12C (R12C/R391H/T458I). Using these variants and the kinase-inactive D329A variant to delineate the contributions of IRAK4's scaffolding and kinase activities to IL1R signaling, we found that the G298D variant is kinase-inactive and expressed at extremely low levels, acting functionally as a null mutation. The R12C compound variant possessed WT kinase activity, but could not interact with myeloid differentiation primary response 88 (MyD88) and IRAK1, causing impairment of IL-1-induced signaling and cytokine production. Quantitation of IL-1 signaling in IRAK4-deficient cells complemented with either WT or the R12C or D329A variant indicated that the loss of MyD88 interaction had a greater impact on IL-1-induced signaling and cytokine expression than the loss of IRAK4 kinase activity. Importantly, kinase-inactive IRAK4 exhibited a greater association with MyD88 and a weaker association with IRAK1 in IRAK4-deficient cells expressing kinase-inactive IRAK4 and in primary cells treated with a selective IRAK4 inhibitor. Loss of IRAK4 kinase activity only partially inhibited IL-1-induced cytokine and NF-κB signaling. Therefore, the IRAK4-MyD88 scaffolding function is essential for IL-1 signaling, but IRAK4 kinase activity can control IL-1 signal strength by modulating the association of IRAK4, MyD88, and IRAK1.

show abstract

Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design

Cited by 113 publications

References 64 publications

Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control

Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control

IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer

Mechanism of dysfunction of human variants of the IRAK4 kinase and a role for its kinase activity in interleukin-1 receptor signaling

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