Sickle cell disease (SCD), a devastating chronic inherited disorder caused by a single amino acid substitution in hemoglobin (Hb), affects approximately 100,000 Americans and millions worldwide. Structurally abnormal Hb in SCD causes red blood cells (RBCs) to become fragile, rigid, and malformed (i.e., sickled). Chronic and excessive RBC hemolysis and microvascular occlusion in SCD results in a diverse set of adverse pathologic effects, including persistent release of reactive oxygen species and an exaggerated pro-inflammatory response from activation of the innate NLRP3 inflammasome pathway. For those suffering from SCD, this can become a vicious cycle in which a persistent pro-inflammatory state precipitates further microvascular occlusion, and consequently, contributes to long-standing inflammation and progressive organ dysfunction. Consequently, SCD patients suffer from a poor quality of life and have a reduced life expectancy. The complex nature of the disease and its clinical manifestations require therapies that can target downstream pathophysiologic effects, of which inflammation plays a key role. Although evidence continues to emerge supporting the potential benefit of anti- inflammatory agents, there are currently no anti-inflammatory drugs approved specifically for the treatment of SCD. The NLRP3 inflammasome is a large multimeric protein complex that, when triggered by a diverse set of danger signals, initiates a profound innate inflammatory response by activating caspase-1 and the proinflammatory cytokine IL-1β. It is clear that excessive drive of the inflammasome pathway plays a key role in the pathogenesis of SCD. A potent and selective drug targeting NLRP3 inflammasome inhibition would provide the most robust inflammatory modulation to benefit SCD patients, far above that which can be achieved with direct inhibition of caspase-1 or IL-1β. The goal of this proposal is to develop our lead therapeutic candidate YQ128, a highly potent oral inflammasome inhibitor to reduce morbidity and improve the prognosis for SCD patients. YQ128 is a bona fide lead drug candidate that represents the culmination of multiple rounds of rational structure-based modification to improve potency, selectivity, and drug-like physiochemical properties of a novel chemical scaffold that blocks formation of the inflammasome complex by interfering with the interaction between NLRP3 and its adaptor protein ASC. Based on a significant body of highly encouraging preliminary in vitro and in vivo data, we have developed a research strategy that will demonstrate proof-of-concept efficacy for this novel approach in a model of microvascular occlusion in transgenic SCD mice. This Phase I study will facilitate a rapid transition to definitive efficacy testing and IND-enabling toxicology studies in Phase II.