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 121 publications

(135 citation statements)

References 64 publications

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“…In a previous publication (7), we reported that IL-1-induced cytokines were minimally impacted by an IRAK4 inhibitor at a concentration of 10 M. However, the inhibitor used in that study had poor physical properties and did not allow us to completely test its pharmacology. The inhibitor PF-06650833 has superior cell potency, is highly selective for IRAK4, and maximally covers IRAK4 at a concentration of 200 nM with no inhibition of other kinases, including IRAK1 (18). Therefore, the data presented in this study substantiate our previous finding of partial inhibition of IL-1-mediated cytokine by an IRAK4 kinase inhibitor.…”

Section: Inhibition Of Irak4 In Primary Human Dermal Fibroblasts Usinsupporting

confidence: 87%

“…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%

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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.

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Section: Inhibition Of Irak4 In Primary Human Dermal Fibroblasts Usinsupporting

confidence: 87%

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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“…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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“…Innate immune signaling has an essential role in inflammation, and the dysregulation of signaling components of this pathway is increasingly being recognized as an important factor in cancer initiation, progression, and metastasis, as well as in autoimmunity. However, among the four IRAKs, only the IRAK4 kinase domain structure has been determined, both alone and in complex with various inhibitors (10,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). No structural information is currently available for IRAK1.…”

Section: Significancementioning

confidence: 99%

Crystal structure of human IRAK1

Wang

Qiao

Ferrao

et al. 2017

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

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Interleukin 1 (IL-1) receptor-associated kinases (IRAKs) are serine/threonine kinases that play critical roles in initiating innate immune responses against foreign pathogens and other types of dangers through their role in Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) mediated signaling pathways. Upon ligand binding, TLRs and IL-1Rs recruit adaptor proteins, such as myeloid differentiation primary response gene 88 (MyD88), to the membrane, which in turn recruit IRAKs via the death domains in these proteins to form the Myddosome complex, leading to IRAK kinase activation. Despite their biological and clinical significance, only the IRAK4 kinase domain structure has been determined among the four IRAK family members. Here, we report the crystal structure of the human IRAK1 kinase domain in complex with a small molecule inhibitor. The structure reveals both similarities and differences between IRAK1 and IRAK4 and is suggestive of approaches to develop IRAK1- or IRAK4-specific inhibitors for potential therapeutic applications. While the IRAK4 kinase domain is capable of homodimerization in the unphosphorylated state, we found that the IRAK1 kinase domain is constitutively monomeric regardless of its phosphorylation state. Additionally, the IRAK1 kinase domain forms heterodimers with the phosphorylated, but not unphosphorylated, IRAK4 kinase domain. Collectively, these data indicate a two-step kinase activation process in which the IRAK4 kinase domain first homodimerizes in the Myddosome, leading to its -autophosphorylation and activation. The phosphorylated IRAK4 kinase domain then forms heterodimers with the IRAK1 kinase domain within the Myddosome, leading to its subsequent phosphorylation and activation.

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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 121 publications

References 64 publications

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

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

IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer

Crystal structure of human IRAK1

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