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Background: IRAK4 plays a pivotal role in the innate immune response, acting downstream of TLRs and IL-1R It exhibits both kinase activity and scaffolding functions, making it a critical target for modulating inflammatory signaling pathways. Traditional IRAK4 kinase inhibitors have shown limited efficacy due to their inability to fully inhibit the scaffolding function of IRAK4. IRAK4 PROTAC offers a novel approach by selectively degrading the entire protein, thereby achieving broader pathway inhibition.
Objectives: This study aimed to discover and characterize a potent and selective oral IRAK4 PROTAC, and evaluate its therapeutic potential for treating autoimmune and inflammatory diseases.
Methods: We developed and extensively characterized SIM0711, an oral IRAK4 PROTAC, in vitro and in vivo . Its activity was compared with either the benchmark IRAK4 PROTAC (KT-474) or the benchmark IRAK4 inhibitor (PF-06650833). Key assays included:
IRAK4 degradation in human PBMCs and fibroblast/keratinocyte cell lines.
IRAK4 degradation kinetics in THP-1 cells or primary monocytes.
Inhibition of pro-inflammatory cytokines (IL-6 and IL-8) in human PBMCs stimulated by LPS or IL-33.
Efficacy in a mouse model of IL-33-induced skin inflammation.
PK/PD, bioavailability, and safety profiles across multiple species.
Results: 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 PF-06650833 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.
Conclusion: These findings establish SIM0711 as a best-in-class IRAK4 PROTAC with the potential to treat a wide range of autoimmune and inflammatory diseases. Its robust IRAK4 degradation, superior anti-inflammatory efficacy, and favorable drug properties support its further development, with an IND submission anticipated in H2 2025.
REFERENCES: NIL.
Acknowledgements: NIL.
Disclosure of Interests: Peng Gu Simcere Pharmaceutical Group Limited, Simcere Pharmaceutical Group Limited, Mengyu Wang Simcere Pharmaceutical Group Limited, Minyun Zhou Simcere Pharmaceutical Group Limited, Qianqian Liang Simcere Pharmaceutical Group Limited, Simcere Pharmaceutical Group Limited, Yuxi Yan Simcere Pharmaceutical Group Limited, Li Sun Simcere Pharmaceutical Group Limited, Yiling Chen Simcere Pharmaceutical Group Limited, Xin Wang Simcere Pharmaceutical Group Limited, Xiaofeng Zhao Simcere Pharmaceutical Group Limited, Simcere Pharmaceutical Group Limited, Feng Tang Simcere Pharmaceutical Group Limited, Simcere Pharmaceutical Group Limited, Shunwei Zhu Simcere Pharmaceutical Group Limited, Simcere Pharmaceutical Group Limited.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (