Cardiovascular disease remains the leading cause of death, worldwide. The most common underlying cause of ischemic heart disease and stroke is atherosclerosis. Three seminal studies, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease (LoDoCo2), and the Colchicine Cardiovascular Outcomes Trial (COLCOT), have proven the hypothesis that atherosclerosis is an inflammatory disease, and that targeting mechanisms of inflammation can reduce major adverse cardiac events independent of lipid lowering. The work proposed here represents a drug discovery and development program designed to target residual inflammatory risk in patients with atherosclerosis. It is in response to the funding opportunity announcement RFA-HL-23-011 titled “Catalyze: Product Definition for Small Molecules and Biologics - Target Identification and Validation, and Preliminary Product/Lead Series Identification (R61/R33).” Interleukin-1β (IL-1β) was the target of canakinumab in the CANTOS trial. Inflammatory cells like activated monocytes and macrophage are a significant source of interleukin-1β in atherosclerotic plaques. Its transcription is under tight control, and maximum expression of this cytokine in inflammatory leukocytes requires adhesion dependent signaling through integrins. Integrins transmit signals into cells through direct interactions between their cytoplasmic domains and intracellular effectors. Integrin β-chain cytoplasmic domains interact directly with the non-receptor tyrosine kinase Syk, which is an essential kinase in the production of IL-1β. In previous work, we determined that β-chain cytoplasmic domain interactions with Syk were druggable, and an antagonist of this interaction could prevent integrin mediated upregulation of IL-1β in monocytes. In the current proposal we seek to extend this work by performing a structure-guided virtual screen of over 10 million compounds to identify potent and cell-permeable drugs that can be used as starting points in drug discovery and development. Our objective in the R61 component of this award is to identify compounds from modeling and molecular dynamics simulations that can be validated in both cell-free, and cell-based assays of integrin:Syk interactions. Once strict “hit” criteria have been met, they will enter into the R33 component of this award mechanism for assessment of potential toxicities, pharmacokinetics, and efficacy in an acute model of inflammation in mice. The studies proposed here will identify a lead series of compounds for drug development, with the ultimate goal being to develop a novel, first-in-class approach to pharmacologically target residual inflammatory risk. CANTOS, LoDoCo2, and COLCOT demonstrated that targeting IL-1β either directly or indirectly is a viable approach to treat residual inflammatory risk in atherosclerosis. The proposed approach would target upstream signals in the regulation of IL-1β in in...