Background/Purpose: IRAK4 plays a pivotal role in the innate immune response by acting downstream of Toll-like receptors (TLRs) and the interleukin-1 receptor (IL-1R), with both kinase activity and scaffolding functions. This dual role makes it a critical target for modulating inflammatory signaling. However, traditional IRAK4 kinase inhibitors have shown limited efficacy due to their inability to disrupt the scaffolding function. IRAK4-targeting PROTACs offer a more comprehensive strategy by inducing selective degradation of IRAK4 protein. Here, we report the discovery and characterization of SIM0711, a potent and selective oral IRAK4 PROTAC for the treatment of autoimmune diseases.

Methods: We developed and extensively characterized SIM0711 through a series of in vitro and in vivo studies. SIM0711 was benchmarked against KT-474 (an IRAK4 PROTAC) and PF-06650833 (a selective kinase inhibitor). IRAK4 degradation and kinetics were assessed in human immune and stromal cells. Downstream cytokine inhibition (IL-6 and/or IL-8) was measured by ELISA followed by TLR4, TLR8, TLR9, and IL-1R stimulation. In vivo efficacy and pharmacodynamic effects on cytokine production were evaluated in multiple mouse models of inflammation. Additionally, oral dosing studies in rodents, dogs, and non-human primates (NHPs) were conducted to characterize IRAK4 degradation, PK/PD relationships, bioavailability, and safety.

Results: In comparison to the benchmark PROTAC KT-474, SIM0711 achieved near-complete IRAK4 degradation in diverse human immune cells and stromal cell lines, with faster degradation kinetics observed in primary human monocytes. Meanwhile, SIM0711 induced more complete inhibition of IL-6 and IL-8 secretion upon TLR4, TLR7, TLR9, and IL-1R activation, outperforming both PF-06650833 and KT-474 in vitro. In vivo, SIM0711 significantly reduced inflammation and demonstrated superior efficacy over KT-474 in multiple mouse models. This enhanced efficacy correlated well with deeper IRAK4 degradation in PBMCs and near-complete suppression of pro-inflammatory cytokine release at the site of inflammation. Additionally, SIM0711 showed improved oral bioavailability, robust IRAK4 degradation ( > 90%), favorable PK/PD properties and good safety profiles across rodents, dogs and NHPs. Notably, SIM0711 exhibited a more balanced tissue distribution than KT-474, with preferential accumulation only observed at the inflamed site, potentially contributing to an improved therapeutic window.

Conclusion: These findings support SIM0711 as a potential best-in-class IRAK4 PROTAC for the treatment of a range of autoimmune diseases. Its robust IRAK4 degradation, superior anti-inflammatory efficacy, and favorable pharmacological profile highlight its strong therapeutic potential. IND submission is expected by Q3 2025.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/discovery-and-characterization-of-sim0711-a-potent-and-selective-irak4-protac-with-improved-efficacy-and-safety/