Discovery and characterization of SIM0711, a potent and selective IRAK4 PROTAC with enhanced efficacy and safety 4626

Abstract Description IRAK4 is a key driver of the innate immune response downstream of TLRs and IL-1R with both kinase and scaffolding functions. Unlike previous kinase inhibitor, IRAK4 PROTAC offers a more effective strategy by selectively degrading IRAK4 protein rendering a more comprehensive pathway inhibition. Here, we reported the discovery and characterization of SIM0711, a potent and selective oral IRAK4 PROTAC, for the treatment of autoimmune diseases. In comparison to benchmark PROTAC KT-474, SIM0711 induced near-complete IRAK4 degradation in diverse primary human immune cells and stromal cell lines, demonstrating faster degradation kinetics in THP-1 cells and primary human monocytes in vitro. In the meantime, SIM0711 also led to deeper inhibition of the pro-inflammatory cytokines IL-6 and IL-8 following the stimulation of LPS, or IL-33 compared to either the kinase inhibitor or KT-474. In vivo, in a mouse model of IL-33-induced skin inflammation, SIM0711 dose-dependently reduced skin inflammation, nearly abolishing downstream IL-5 secretion at the inflammation site. Furthermore, SIM0711 demonstrated improved bioavailability, favorable PK/PD characteristics, and good safety profiles across multiple species. Taken together, these data support the further development of SIM0711 as a potential BIC IRAK4 PROTAC for treating a range of inflammatory and autoimmune diseases with expected IND submission in H2 2025. Funding Sources Topic Categories Therapeutic Approaches to Autoimmunity (THER)