{"id":4073,"date":"2024-07-15T14:02:21","date_gmt":"2024-07-15T14:02:21","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/poster\/irak4-inhibitor-modalities\/"},"modified":"2026-01-22T15:30:19","modified_gmt":"2026-01-22T15:30:19","slug":"irak4-inhibitor-modalities","status":"publish","type":"poster","link":"https:\/\/www.sygnaturediscovery.com\/fr\/poster\/irak4-inhibitor-modalities\/","title":{"rendered":"Early Comparison of the in vitro to in vivo Translation of Different IRAK4 Inhibitor Modalities"},"content":{"rendered":"<p><span style=\"font-family: arial, helvetica, sans-serif;\">Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) is a master regulator of innate immunity, playing a central role in both toll-like receptor and interleukin-1 (IL-1) inflammation. Proteolysis targeting chimeras (PROTACs) are hetero-bifunctional molecules that degrade target proteins using the ubiquitin-proteasome system. This novel therapeutic modality inhibits IRAK4 and has the potential additional efficacy due to removing the protein&rsquo;s scaffolding and kinase functions compared to kinase activity-only inhibitors like PF-06650833. A specific IRAK4 PROTAC, KT-474, has recently entered Phase 2 clinical trials to treat hidradenitis suppurativa and other conditions.\u00a0\u00a0<\/span><\/p>\n<p><span style=\"font-family: arial, helvetica, sans-serif;\">This scenario allowed us to compare the <i>in vitro<\/i> to <i>in vivo<\/i> translation of an IRAK4 degrader with an activity inhibitor. We began by evaluating the ability of KT-474 and PF-06650833 to degrade IRAK4 and inhibit downstream LPS-driven cytokine production <i>in vitro<\/i> using the THP-1 cell line and human peripheral blood monocytes (PBMCs). We then determined the PK of KT-474 and PF-06650833 before profiling both compounds in a mouse LPS model of acute inflammation.\u00a0\u00a0<\/span><\/p>\n<p><span style=\"font-family: arial, helvetica, sans-serif;\">Our findings reveal that KT-474 potently degrades IRAK4 (0.88 nM DC50, 101% Dmax) and inhibits LPS\/R848-driven PBMC IL-6 production. Notably, the inhibitory effect of KT-474 is maintained following its removal, unlike PF-06650833, demonstrating the longevity of this therapeutic modality over conventional kinase activity inhibition. In mouse PK, KT-474 reaches a Cmax after 2 hours, with measurable plasma levels up to 24 hours, showcasing its unique features and potential benefits.\u00a0\u00a0<\/span><\/p>\n<p><span style=\"font-family: arial, helvetica, sans-serif;\">In summary, we have demonstrated that KT-474&rsquo;s degradation of IRAK4 is an effective therapeutic modality for inhibiting cytokine generation <i>in vitro<\/i>, potentially with greater efficacy and longevity than conventional kinase activity inhibitors for treating various autoimmune diseases. Our next steps are to characterize the <i>in vivo<\/i> PK\/PD for these different IRAK4 inhibitor modalities to determine if KT-474 exhibits greater longevity and efficacy, as shown <i>in vitro<\/i>.\u00a0<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"","protected":false},"featured_media":2776,"template":"","category":[681,685,727,737,686,743],"class_list":["post-4073","poster","type-poster","status-publish","has-post-thumbnail","hentry","category-bioscience","category-in-vivo-pharmacology","category-in-vivo-pk-pd","category-inflammation-immunology-models","category-modalities","category-tpd"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.8 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>in vitro to in vivo Translation of Different IRAK4 Inhibitor Modalities<\/title>\n<meta name=\"description\" content=\"This scenario allowed us to compare the in vitro to in vivo translation of an IRAK4 degrader with an activity 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