14 April 2025
Toll-like receptors (TLRs) are important in initiating inflammatory signaling in the lungs in response to pathogens and environmental triggers. Bacterial lipopolysaccharide (LPS) primarily activates TLR4, while viral stimuli preferentially engage TLR7/8. Previous pre-clinical studies have demonstrated that stimulating TLR4 and TLR7/8 in human lung tissue explants leads to pro-inflammatory effects. Activation of TLRs leads to the recruitment of adaptor proteins, which in turn can recruit interleukin-1 receptor-associated kinases (IRAKs). These kinases, including IRAK1, 2, 3, and 4, play a crucial role in the immune response to pathogens. IRAK4, in particular, is crucial for regulating IL-1R and TLR signaling pathways, and it plays a significant role in inflammation, autoimmunity, and drug resistance. Developing inhibitors and degraders for IRAK4 could be a valuable therapeutic approach for these conditions, ultimately creating new research strategies for inflammation and related diseases.
To investigate the roles of IRAK4 in vitro and in vivo, we offer the specific and selective IRAK4 inhibitor BI1543673, free of charge via opnMe. Additionally, we are providing a structurally similar but inactive analogue called BI-4326 as a negative control. Interested researchers will receive these molecules for free and have full ownership of their results. We encourage researchers to publish their findings as part of our commitment to open science.
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About BI1543673:
BI1543673 is a potent IRAK4 inhibitor with a unique selectivity profile, including selectivity versus IRAK1. in vitro, BI-4737 exhibits a potency in the single-digit nanomolar range on human IRAK4 and in the triple-digit nanomolar range on human IRAK1. BI1543673 is well soluble and exhibits medium plasma protein binding. It also demonstrates a favorable metabolic stability profile across different species. Due to high efflux ratios observed in permeability assays, the distribution of BI1543673 into the brain is limited, indicating restricted crossing of the blood-brain barrier. BI1543673 shows acceptable to low oral bioavailability in mouse and rat, respectively. For in vivo studies in mice, it is recommended to administer an oral dose of 300 mg/kg in 0.5% hydroxyethylcellulose (pH 4).
About opnMe:
opnMe.com, the open innovation portal of Boehringer Ingelheim, fosters science and collaboration initiatives in areas of high unmet medical need. As part of our first pillar, the “Molecules to Order”, we share well-characterized tool compounds free of charge with no IP strings attached. These are complemented by “Molecules for Collaboration” where we offer access to unprecedented, often unpublished molecules, together with an attractive funding package. Interested scientists are invited to submit testable research hypotheses with these assets in novel diseases or combinations. With our “opn2EXPERTS” and “techMATCH” programs, we enlist scientific advice on key biologic issues to fuel further drug discovery and deliver novel solutions that benefit unmet patient needs. Learn more about our recent call on the role of GluN3A in psychiatric symptoms. Our current opn2TALENTS PostDoc grant for 3D-modelling and potency predictions, provides an opportunity for high-caliber talents to pitch their scientific approaches for well-defined research questions to conduct their research at our discovery research site Biberach, Germany.