Grant: Alliance Grants

· CHALLENGE. This proposal addresses the challenge of inaccuracies in quantifying the binding strength between drug candidates and their therapeutic targets, expressed by the equilibrium dissociation constant Kd. Accurate Kd determination is pivotal for informed decision-making in drug development. Inaccuracies can result in misranking drug candidates, advancing weak compounds, and overlooking promising ones, leading to costly inefficiencies, high development costs, and missed opportunities. NATURE. To overcome this challenge, we propose integrating our innovative approach, "Accurate Constants via Transient Incomplete Separation" (ACTIS), with Mass Spectrometry (MS). ACTIS rapidly separates target-bound candidates from unbound ones within a capillary, generating concentration profiles that encode data for accurate Kd determination. Combining ACTIS with MS enables label-free detection, enhancing the accuracy and versatility of Kd determinations. We will address the scientific and technological challenges of this integration through rigorous theoretical and experimental research. OUTCOMES. This project will deliver breakthrough knowledge and develop the ACTIS-MS technology for accurately ranking drug candidates. Additionally, we will train a diverse team of highly skilled researchers equipped to advance this innovation in industrial and academic settings. IMPORTANCE. These advancements are crucial for the pharmaceutical discovery industry and manufacturers of MS instrumentation, particularly our industry partner, SCIEX - a flagship of Canadian industry and a global leader in MS technologies. This partnership uniquely positions SCIEX at the forefront of innovation by expanding its technology portfolio into new pharmaceutical applications. BENEFITS. The results will drive domestic production of advanced analytical instrumentation, creating new R&D and manufacturing jobs. Our advancements will reduce drug discovery costs and timelines, ultimately improving Canadians' health and well-being.