BGB-45035, a selective IRAK4 CDAC, demonstrated fast IRAK4 degradation and strong signaling inhibition, and superior efficacy in preclinical disease models 2529

Abstract Description IRAK4 is the key kinase downstream of toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R), both of which have been implicated in multiple immune and inflammatory diseases. We have identified BGB-45035 as a novel and highly selective Cereblon-based IRAK4 CDAC (chimeric degradation activating compound), and compared it with KT-474, the leading IRAK4 degrader being developed clinically. BGB-45035 achieved maximum IRAK4 degradation at 5 h while KT-474 reached maximum degradation at 24 h, with stronger downstream MAPK pathway inhibition. The faster and deeper degradation kinetics induced by BGB-45035 was further illustrated using a real-time degradation reporter assay system. To compare the biological effect of the two compounds when maximum IRAK4 degradation could be achieved, BGB-45035 and KT-474 were administrated to mice via a pre-treatment regimen. BGB-45035 achieved stronger inhibition of CXCL1 induced by hIL-36g, and better efficacy in IL-36-induced skin inflammatory disease model and in IMQ-induced psoriasis model. In rat CIA model, BGB-45035 showed robust efficacy in alleviating disease development. Furthermore, BGB-45035 demonstrated better efficacy than KT-474 in IL-33-induced skin inflammatory disease model with stronger inhibition of ear IL-5 and Th2 cells in ear draining lymph node. These data enlightened the contribution of faster and deeper degradation to robust biological effects of IRAK4 degraders. Topic Categories Therapeutic Approaches to Autoimmunity (THER)