S4-02-06: Integrative approach targeting neuroinflammation

Abstract

Background: Neuroinflammation as a component of CNS disease is a complex process that involves a diversity of changes in products produced by glia. One change is the increased production of proinflammatory cytokines in response to diverse stressors. Clinical observations and preclinical animal studies identify increased cytokine production as a potential contributor to disease progression, requiring that it be tested as a potential drug discovery target for CNS disorders such as Alzheimer’s disease (AD). Because restoration of homeostasis is the goal, candidate therapies must be selective in their action (i.e., NOT pan-suppressors of glia function). Current FDA-approved drugs that modulate cytokine function are macromolecules, which have disadvantages for chronic CNS disorders. Therefore, there is a critical unmet need for small molecule, orally active, brain-penetrant compounds that can reduce excessive proinflammatory cytokine production by glia back towards basal levels with resultant improvement in neurologic outcomes. To address this need, we are using a de novo synthetic chemistry platform integrated with hierarchal biology screening to develop candidate compounds that attenuate excessive proinflammatory cytokine production and modify disease progression in animal models. Methods: We refer to the approach as use of “smart chemistry” integrated with “smart biology”. An inactive core scaffold was subjected to focused chemical diversification based on chemoinformatics and pharmacoinformatics to generative novel compounds that were prioritized based on screening their promise for metabolic stability, oral bioavailability, brain uptake, and lack of toxicity. Qualified compounds were subjected to efficacy testing in animal models. Results: Novel candidate compounds emerged within an accelerated timeline and limited budget. The unbiased, function-driven approach yielded one group of analogs referred to as the Minozac family, whereas the single molecular target approach that was focused on a protein kinase candidate yielded the Minokine family of compounds. Both Minozac and Minokine are efficacious in an AD-relevant animal model. Conclusions: The integrative approach, being increasingly adopted in academia and industry, allows for rapid and efficient discovery of novel small molecules that are candidates for therapeutic development campaigns focused on modification of disease progression.