Discovery of 3g as an Orally Bioavailable,TIR Domain Selective, and Potent MyD88 Inhibitor for the Treatmentof Acute Lung Injury

Abstract Myeloid differentiation factor 88 (MyD88) plays a pivotal role in the inflammatory response. However, the number of MyD88 inhibitors is limited, and the effectiveness of current inhibitors is constrained, hindering the progress of clinical research. Herein, thirty-nine novel MyD88 inhibitors were developed based on our previously discovered lead compound c17, and the potent compound 3g was identified using ELISA and DSF assays. Compound 3g specifically and selectively targets the TIR domain of MyD88 rather than its DD domain, thereby preventing MyD88 self-polymerization and interaction with TLRs, which suppresses the activation of MAPK and NF-κB pathways. 3g exhibits a bioavailability of 63% and shows no substantial in vivo toxicity, maintaining notable stability in plasma and digestive juices. Moreover, 3g demonstrated significant anti-inflammatory efficacy and effectively mitigated ALI symptoms in CLP and LPS-induced ALI models. These data indicate that 3g possesses considerable potential as a MyD88 inhibitor for the treatment of ALI.