IRAK4 Inhibitor (Xunhe Pharmaceutical)

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that mediates interleukin-1 and Toll-like receptor (TLR) signaling. IRAK4 drives the activation of nuclear factor kappa B (NF-κB), which promotes cell survival, inflammation, and proliferation. Aberrant activation of IRAK4 and TLR signaling has been implicated in multiple malignancies. At the 3rd Annual IRAK4 in Cancer Symposium, experts discussed the role of IRAK4 in cancer biology, the potential for synergism between IRAK4 inhibition and other treatments to overcome resistance, and how IRAK4 inhibition may improve clinical outcomes. Preclinical data were presented demonstrating the activity of IRAK4 inhibition alone or in combination with other anticancer agents in acute myeloid leukemia, myelodysplastic syndrome, non-Hodgkin lymphoma, primary central nervous system lymphoma, melanoma brain metastases, gastrointestinal cancers, and pancreatic ductal adenocarcinoma. Clinical data from the targeted small-molecule IRAK4 inhibitor emavusertib (CA-4948) were presented, including data from the TakeAim Leukemia and TakeAim Lymphoma trials of emavusertib in myeloid and lymphoid malignancies, respectively, and preliminary data from trials of emavusertib in multiple solid tumors. The meeting closed with expert discussion of the emerging profile of IRAK4 inhibition in cancers and the potential for IRAK4 inhibition to improve outcomes across both solid and liquid tumors.

Interleukin-1 receptor-associated kinase 4 (IRAK4) activity mediates pro-inflammatory signaling and cytokine production downstream of toll-like and interleukin-1 receptors (TLR, IL-1R). Selective IRAK4 inhibitors have generated interest as potential treatments for inflammatory diseases. Herein, we report the discovery of GS-5718 (edecesertib), a potent, selective, orally bioavailable IRAK4 inhibitor. Key to this endeavor were efforts undertaken to improve the chemical series' profile after a significant hERG liability was encountered for an early compound. GS-5718 was safe and well-tolerated in IND-enabling preclinical animal toxicity studies, demonstrated efficacy in a mouse NZB lupus model, and additionally demonstrated human pharmacokinetic properties suitable for once-daily administration. Edecesertib is currently under clinical evaluation for the treatment of lupus.