2,804
Views
31
CrossRef citations to date
0
Altmetric
Review

Investigational IRAK-4 inhibitors for the treatment of rheumatoid arthritis

, &
Pages 475-482 | Received 07 Nov 2019, Accepted 03 Apr 2020, Published online: 17 Apr 2020

References

  • Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016 Oct 22;388(10055):2023–2038.
  • Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet. 2009 Feb 21;373(9664):659–672.
  • Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review. Semin Arthritis Rheum. 2006 Dec;36(3):182–188.
  • Emery P, Breedveld FC, Dougados M, et al. Early referral recommendation for newly diagnosed rheumatoid arthritis: evidence based development of a clinical guide. Ann Rheum Dis. 2002 Apr;61(4):290–297.
  • Schoels M, Knevel R, Aletaha D, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search. Ann Rheum Dis. 2010 Apr;69(4):638–643.
  • Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011 Mar;70(3):404–413.
  • Singh JA, Saag KG, Bridges SL Jr., et al. 2015 American College of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016 Jan;68(1):1–26.
  • Smolen JS, Landewe R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017 Jun;76(6):960–977.
  • Yu C, Jin S, Wang Y, et al. Remission rate and predictors of remission in patients with rheumatoid arthritis under treat-to-target strategy in real-world studies: a systematic review and meta-analysis. Clin Rheumatol. 2019 Mar;38(3):727–738.
  • Giacomelli R, Afeltra A, Alunno A, et al. International consensus: what else can we do to improve diagnosis and therapeutic strategies in patients affected by autoimmune rheumatic diseases (rheumatoid arthritis, spondyloarthritides, systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome and Sjogren’s syndrome)? The unmet needs and the clinical grey zone in autoimmune disease management. Autoimmun Rev. 2017 Sep;16(9):911–924.
  • Giacomelli R, Afeltra A, Alunno A, et al. Guidelines for biomarkers in autoimmune rheumatic diseases - evidence based analysis [Review]. Autoimmun Rev. 2019 Jan;18(1):93–106.
  • Mangoni AA, Zinellu A, Sotgia S, et al. Protective effects of methotrexate against proatherosclerotic cytokines: a review of the evidence. Mediators Inflamm. 2017;2017:9632846.
  • Taylor PC, Moore A, Vasilescu R, et al. A structured literature review of the burden of illness and unmet needs in patients with rheumatoid arthritis: a current perspective. Rheumatol Int. 2016;36(5):685–695.
  • Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2(8):675.
  • Bhide RS, Keon A, Weigelt C, et al. Discovery and structure-based design of 4, 6-diaminonicotinamides as potent and selective IRAK4 inhibitors. Bioorg Med Chem Lett. 2017;27(21):4908–4913.
  • Li X. IRAK4 in TLR/IL‐1R signaling: possible clinical applications. Eur J Immunol. 2008;38(3):614–618.
  • Suzuki N, Suzuki S, Yeh W-C. IRAK-4 as the central TIR signaling mediator in innate immunity. Trends Immunol. 2002;23(10):503–506.
  • Gobin K, Hintermeyer M, Boisson B, et al. IRAK4 deficiency in a patient with recurrent pneumococcal infections: case report and review of the literature. Front Pediatr. 2017;5:83.
  • Picard C, Puel A, Bonnet M, et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science. 2003;299(5615):2076–2079.
  • Suzuki N, Suzuki S, Duncan GS, et al., Severe impairment of interleukin-1 and toll-like receptor signalling in mice lacking IRAK-4. Nature. 2002;416(6882):750.
  • Ku C-L, Von Bernuth H, Picard C, et al. Selective predisposition to bacterial infections in IRAK-4–deficient children: IRAK-4–dependent TLRs are otherwise redundant in protective immunity. J Exp Med. 2007;204(10):2407–2422.
  • Yang K, Puel A, Zhang S, et al. Human TLR-7-, −8-, and −9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses. Immunity. 2005 Nov;23(5):465–478.
  • Picard C, von Bernuth H, Ghandil P, et al., Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore). 2010;89(6):403–425.
  • von Bernuth H, Picard C, Puel A, et al. Experimental and natural infections in MyD88- and IRAK-4-deficient mice and humans. Eur J Immunol. 2012 Dec;42(12):3126–3135.
  • Della Mina E, Borghesi A, Zhou H, et al. Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E514–E523.
  • Kawagoe T, Sato S, Matsushita K, et al. Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat Immunol. 2008 Jun;9(6):684–691.
  • Kobayashi K, Hernandez LD, Galán JE, et al. IRAK-M is a negative regulator of toll-like receptor signaling. Cell. 2002 Jul 26;110(2):191–202.
  • Lye E, Mirtsos C, Suzuki N, et al. The role of interleukin 1 receptor-associated kinase-4 (IRAK-4) kinase activity in IRAK-4-mediated signaling. J Biol Chem. 2004 Sep 24;279(39):40653–40658.
  • Lin S-C, Lo Y-C, Wu H. Helical assembly in the MyD88–IRAK4–IRAK2 complex in TLR/IL-1R signalling. Nature. 2010;465(7300):885.
  • Cao Z, Xiong J, Takeuchi M, et al. TRAF6 is a signal transducer for interleukin-1. Nature. 1996;383(6599):443.
  • Kollewe C, Mackensen A-C, Neumann D, et al. Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signaling. J Biol Chem. 2004;279(7):5227–5236.
  • Choudhary GS, Bhagat TD, Samson MES, et al. Efficacy of novel IRAK4 inhibitor CA4948 in AML and MDS [abstract]. Cancer Res. 2017;17(13Suppl):Abstractnr 127.
  • Kawagoe T, Sato S, Jung A, et al. Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling. J Exp Med. 2007;204(5):1013–1024.
  • De S, Karim F, Kiessu E, et al. Mechanism of dysfunction of human variants of the IRAK4 kinase and a role for its kinase activity in interleukin-1 receptor signaling. J Biol Chem. 2018 Sep 28;293(39):15208–15220.
  • Hubbard LLN, Moore BB. IRAK-M regulation and function in host defense and immune homeostasis. Infect Dis Rep. 2010;2(1):e9.
  • Sode J, Vogel U, Bank S, et al. Confirmation of an IRAK3 polymorphism as a genetic marker predicting response to anti-TNF treatment in rheumatoid arthritis. Pharmacogenomics J. 2018 Jan;18(1):81–86.
  • Lech M, Kantner C, Kulkarni OP, et al. Interleukin-1 receptor-associated kinase-M suppresses systemic lupus erythematosus. Ann Rheumatic Dis. 2011;70(12):2207–2217.
  • Kimura H, Inukai Y, Takii T, et al. Molecular analysis of constitutive IL-1alpha gene expression in human melanoma cells: autocrine stimulation through NF-kappaB activation by endogenous IL-1alpha. Cytokine. 1998 Nov;10(11):872–879.
  • Singh AK, Fechtner S, Chourasia M, et al. Critical role of IL-1α in IL-1β–induced inflammatory responses: cooperation with NF-κBp65 in transcriptional regulation. FASEB J. 2019;33(2):2526–2536.
  • Dinarello CA, Ikejima T, Warner SJ, et al. Interleukin 1 induces interleukin 1. I. Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro. J Immunol. 1987 Sep 15;139(6):1902–1910.
  • Noack M, Miossec P. Selected cytokine pathways in rheumatoid arthritis. Semin Immunopathol. 2017 Jun 1;39(4):365–383.
  • Lacerte P, Brunet A, Egarnes B, et al. Overexpression of TLR2 and TLR9 on monocyte subsets of active rheumatoid arthritis patients contributes to enhance responsiveness to TLR agonists. Arthritis Res Ther. 2016;18:10.
  • Chamberlain ND, Kim S-J, Vila OM, et al. Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes. Ann Rheum Dis. 2013;72(3):418–426.
  • Huang Q, Ma Y, Adebayo A, et al. Increased macrophage activation mediated through toll-like receptors in rheumatoid arthritis. Arthritis Rheum. 2007 Jul;56(7):2192–2201.
  • Goh FG, Midwood KS. Intrinsic danger: activation of Toll-like receptors in rheumatoid arthritis. Rheumatology. 2011;51(1):7–23.
  • Wang J, Yan S, Yang J, et al. Non-coding RNAs in rheumatoid arthritis: from bench to bedside. Front Immunol. 2019;10:3129.
  • Tavasolian F, Abdollahi E, Rezaei R, et al. Altered expression of MicroRNAs in rheumatoid arthritis. J Cell Biochem. 2018 Jan;119(1):478–487.
  • Mu N, Gu J, Huang T, et al. A novel NF-kappaB/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis. Sci Rep. 2016 Jan 29;6:20059.
  • Pauley KM, Satoh M, Chan AL, et al. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther. 2008;10(4):R101.
  • Wang Y, Zheng F, Gao G, et al. MiR-548a-3p regulates inflammatory response via TLR4/NF-kappaB signaling pathway in rheumatoid arthritis. J Cell Biochem. 2019 Jan 6;20(2):1133–1140.
  • Wang Z, Liu J, Sudom A, et al. Crystal structures of IRAK-4 kinase in complex with inhibitors: a serine/threonine kinase with tyrosine as a gatekeeper. Structure. 2006 Dec 01;14(12):1835–1844.
  • Chaudhary D, Robinson S, Romero DL. Recent advances in the discovery of small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders: miniperspective. J Med Chem. 2014;58(1):96–110.
  • Wang Z, Wesche H, Stevens T, et al. IRAK-4 inhibitors for inflammation. Curr Top Med Chem. 2009;9(8):724–737.
  • McElroy WT. Interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors: an updated patent review (2016–2018). Expert Opin Ther Pat. 2019 Apr;29(4):243–259.
  • Bothe U, Wengner AM, Siebeneicher H, et al. Combinations of Inhibitors of IRAK4 with Inhibitors of BTK. Google Patents; 2018.
  • Lee KL, Ambler CM, Anderson DR, et al. Discovery of clinical candidate 1-{[(2 S, 3 S, 4 S)-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. J Med Chem. 2017;60(13):5521–5542.
  • Gummadi VR, Samajdar S. Bicyclic heterocyclyl derivatives as irak4 inhibitors. Google Patents; 2018.
  • Booher RN, Nowakowski GS, Patel K, et al. Preclinical activity of IRAK4 kinase inhibitor CA-4948 alone or in combination with targeted therapies and preliminary phase 1 clinical results in Non-Hodgkin lymphoma. San Diego: Annual Meeting of the American Society of Hematology; 2018.
  • Booher RN, Samson MEXu G-X, et al.Efficacy. Of the irak4 inhibitor ca-4948 in patient-derived xenograft models of diffuse large b cell lymphoma. Atlanta: Annual Meeting of the American Association for Cancer Research; 2017.
  • Booher R, Samson M, Borek M, et al. CA-4948, an IRAK4/FLT3 inhibitor, showed antileukemic activity in mouse models of FLT3 wild-type and FLT3 mutated acute myeloid leukemia (AML): PS991. HemaSphere. 2019;3:445–446.
  • Rosenthal AC, Tun HW, Younes A, et al. Phase 1 study of CA-4948, a novel inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) in patients (pts) with r/r non-Hodgkin lymphoma. J clin oncol. 2019;37(15_suppl):e19055.
  • Lange M, Wengner AMBothe U, et al. Preclinical evaluation of a novel interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor in combination with PI3K inhibitor copanlisib or BTK inhibitors in ABC-DLBCL. Chicago: Annual Meeting of the American Association for Cancer Research; 2018.
  • Danto S, Shojaee NLi C, et al., Editors. Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a Novel, potentially first-in-class inhibitor of interleukin-1 receptor associated kinase-4 (IRAK-4) in healthy subjects. Abstract 544. San Diego: American College of Rheumatology Annual Meeting; 2017.
  • Younes A, Nowakowski G, Rosenthal A, et al. Phase 1 study of CA-4948, a novel inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) in patients with R/R Non-Hodgkin Lymphoma (NHL). Clin Lymphoma Myeloma Leukemia. 2019 Sep;19(Supplement 1):S256–S257.
  • Danto SI, Shojaee N, Singh RSP, et al., editors. Efficacy and safety of the selective interleukin-1 receptor associated kinase 4 inhibitor, PF-06650833, in patients with active rheumatoid arthritis and inadequate response to methotrexate, abstract number 2909. American College of Rheumatology Annual Meeting; 2019; Atlanta.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.