Introduction: The innate immune response enables cells to quickly respond to inflammatory cytokines by mounting the initial protective response through the activation and downstream function of the interleukin-1 receptor activated kinase (IRAK) family. Small molecule kinase inhibitors of IRAK4 have long been sought to block this response in auto-inflammatory diseases such as lupus. Methods: In an effort to block disease progression, several scaffolds of IRAK4 small molecule inhibitors were explored using structure-based drug design. The discovery and development of our lead scaffold along with how it was influenced by other scaffolds will be presented including structural understanding of the binding site and in vivo PK and PD. Results: Through medicinal chemistry efforts including structure-based drug design, analysis of physicochemical properties and application of drug development principles, a series of potent and selective IRAK4 inhibitors were discovered. These molecules proved stable across species and showed compelling activity in in vivo models for inflammation. Discussion: The discovery, development and in vivo profile of our lead IRAK4 small molecule inhibitors will be disclosed for the first time.

Small molecule inhibitors of IRAK4

2019 Fall National Meeting

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