IRAK4 is a member of the IRAK family of serine-threonine kinases which signals downstream of toll-like receptors (TLRs) and IL-1 receptors.  TLRs are centrally critical to innate immune system defense due to their ability to recognize molecular patterns associated with various bacterial and viral pathogens.  In addition, these pattern recognizing receptors also detect damage-associated molecular pathogens (DAMPs) generated in the course of chronic autoimmune disease states such as lupus.  Activation of the TLRs (except TLR3 and to a lesser degree TLR4) by these DAMPs starts a complex signaling cascade of adaptor protein recruitment and IRAK4 activation.  Subsequent signaling via downstream kinases leads to NF-kB activation and cytokine expression.   The location of IRAK4 downstream of these innate immune system signaling receptors has resulted in significant interest in therapeutic targeting of IRAK4 in autoimmune diseases.  Herein, we present the discovery, SAR, and potency optimization of a pyridine amide series of IRAK4 inhibitors.  The structural basis of inhibition will be detailed with X-ray co-crystal structures of select compounds.  Additionally, kinase selectivity optimization and in vivo efficacy in a murine model of lupus will be presented.<br/>

Identification and <i>in vivo</i> evaluation of novel IRAK4 inhibitors in murine models of lupus

256th National Meeting (2018)

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Identification and in vivo evaluation of novel IRAK4 inhibitors in murine models of lupus