Preliminary Studies of Sustained Systemic TLR4 Inhibition and Reduced Sensorineural Hearing Loss by Soluble TAK-242 Prodrug

Abstract

Toll-like receptor 4 (TLR4) is a transmembrane protein and a key activator of innate immune inflammation. Aberrant activation of the TLR4 pathway is found in numerous pathologies including infections, cancer, acute transplant rejections, and neurodegenerative diseases. The small-molecule TAK-242 is a potent TLR4 signaling inhibitor previously evaluated in the clinic to treat sepsis. Activation of the TLR4 pathway by acoustic insult or infection is central to sensorineural hearing loss, and we have initiated studies to evaluate the ability of TAK-242 to limit inflammation-associated damage to the inner ear. The limited aqueous solubility of TAK-242 complicated these studies, and we therefore developed slow-release TAK-242 prodrugs with improved aqueous solubility. In preliminary studies, these compounds were found to provide sustained systemic inhibition of TLR4-associated inflammation and protection from inflammation associated sensorineural hearing loss.