Abstract The overall goal of Jacaranda Biosciences, Inc. (JBI) is to develop compounds that will treat a broad range of hearing loss indications, a sorely unmet need. In this initial SBIR project, we will use our expertise in medicinal chemistry, cell biology and hearing physiology to functionally test and chemically optimize a series of novel compounds that modulate the unfolded protein response (UPR). These compounds, made and IP protected by JBI, will be used to demonstrate initial efficacy to prevent noise-induced hearing loss in our mouse model. Noise-induced hearing loss (NIHL) is a profound public health problem, affecting over 40 million Americans and causing the loss of 4 million disability-adjusted life years worldwide from occupational exposure annually. HL is also a significant risk factor for dementia, underscoring the expanded morbidity of this disorder. 27% of NIHL is from acute sound exposure, whereas 23% occurs from sub- acute or chronic exposure to sound, suggesting that interventions that target the mechanisms that underlie acute or sub-acute HL can make an immediate and transformative clinical impact for this large and inadequately treated patient population. Through our novel work in genetic and noise-induced animal models of hearing loss, we have discovered that homeostatic regulation of the UPR in the endoplasmic reticulum (ER) of cochlear hair cells is essential to prevent dysregulated over-activation of the UPR and subsequent hair cell death and hearing loss. Moreover, we have shown in published data that regulating the UPR through treatment with publicly available eiF2B activators and CHOP inhibitors (UPR pathway proteins) can prevent hair cell death and hearing loss in both noise-induced and genetic HL models. To take advantage of these insights, we will develop and optimize a proprietary series of novel eiF2B activators for eventual treatment in a large patient population. Our Aims are to (1) optimize the efficacy and physicochemical properties of our IP-protected, novel compounds; (2) Test whether the optimized compounds can lessen apoptosis and UPR over-activation in our cell-based models; and (3) determine whether these compounds prevent hearing loss and cochlear injury in our established animal model of acoustic overstimulation.