Background/Purpose:   Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key mediator of the innate immune response orchestrated by interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), IL-33 receptor (IL-33R), and Toll-like receptors (TLRs).  IRAK4 activation is mediated by MYD88, a common signaling adaptor protein downstream of these receptors.  Mutations leading to inactivation or activation of MYD88 have been reported in patients with immune deficiencies and cancer, respectively.  In addition, IRAK4-deficient humans are protected from chronic inflammatory diseases.  Thus, IRAK4 is an attractive therapeutic target for the treatment of autoimmune diseases such as lupus.  Historically, identification of potent and selective IRAK4 inhibitors has been challenging due to structural features in the catalytic binding site that block access to the hydrophobic back pocket.  We have developed new structure-activity relationship (SAR) insights, including the identification of unstable (high-energy) hydration sites, which guide the design of potent and selective small molecule ligands.

Methods:   Using this innovative structure-based approach, we designed, synthesized and tested small molecule inhibitors based on hits originated from a virtual screen.  These novel compounds were profiled for IRAK4 kinase inhibition, selectivity, and drug-like properties.  Furthermore, selected compounds were tested in THP1 cells, human peripheral blood mononuclear cells (hPBMCs) and whole blood for impact on LPS-, IL-1-, R848-, and/or CpG-mediated signaling.  The inhibitors were also tested in vivo in acute LPS challenge and chronic collagen induced arthritis (CIA) models.

Results:   Here, we feature three highly potent, selective IRAK4 inhibitors, ND-346, ND-2110 and ND-2158. The K_is of ND-346, ND-2110, and ND-2158 for IRAK4 are 50, 7.5 and 1 nM, respectively. These compounds are highly selective against 334 kinases, and are potent inhibitors of IL-1-induced IRAK1 degradation in MRC5 cells, LPS-, IL-1-, R848 (TLR-7 agonist)- and CpG (TLR-9 agonist)-induced cytokine production in hPBMCs and whole blood.  Furthermore, these compounds are efficacious in the acute LPS challenge model in vivo, and ND-346 shows efficacy in rat CIA at 10 mg/kg (PO, QD).

Conclusion: Utilizing unique and innovative structure-based drug design, we have rapidly discovered potent and selective IRAK4 inhibitors as potential drug candidates for the treatment of chronic rheumatic diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-highly-potent-and-selective-interleukin-1-receptor-associated-kinase-4-inhibitors-for-the-treatment-of-rheumatic-diseases/