STING Inhibitor Discovery for Rare and Common Autoimmune Diseases

Discoverybiomed, Inc., Birmingham AL

Investigators

Abstract

Principal Investigators for Small Business: DiscoveryBioMed, Inc. (DBM) and Nitor Therapeutics, Inc. (Nitor) Project Summary Abstract The over-arching commercial goal for this Nitor Therapeutics, Inc. (Nitor) and DiscoveryBioMed, Inc. (DBM) collaboration is to discover and validate Stimulator of Interferon Genes or ?STING? inhibitor ligands in a novel high-throughput screening (HTS) and validation-based Critical Path of bioassays. Aberrant activation of the STING pathway by self DNA and ?gain of function? mutations in the STING protein dimer can lead to autoimmune disease. Therefore, we hypothesize that STING inhibitory ligands may be a promising new strategy for the treatment of autoimmune and inflammatory diseases in which suppression of the type I IFN pathway may show therapeutic benefit. The Nitor and DBM collaboration has designed a Critical Path of cell- based bioassays with HTS and validation bioassay steps so as to discover STING inhibitor ligands from a de novo screen of a diverse small molecule library derived from 8 different commercial vendors and from a targeted screen of nucleosides/nucleotides from our collaborators at TheraChem. Preliminary data is presented from a pilot screen of approximately 2,000 compounds and from early validation steps scripted within our Critical Path. Milestone 1 focuses on optimizing and cementing our STING Inhibitor HTS and Validation Critical Path. Later efforts in Milestone 1 will validate these STING inhibitors on additional reporter cell lines with more physiological relevance (a THP-1 monocytic cell line stably expressing the STING reporter) and on more relevant diseased human PBMCs isolated from lupus patients. Our validated STING inhibitor ligands will be evaluated by assessing the effect of the inhibitor ligand on the production and secretion of interferon-? (IFN-?) and other secreted inflammatory mediators in response to cGAMP. Milestone 2 will focus on the full HTS campaign to discover and validate novel small molecule STING inhibitors. Chemoinformatics analysis of the validated hits will be performed throughout the HTS campaign so as to identify emerging hit chemical series rapidly. We will then re-profile ?best in class? small molecules from each chemical series of family where a common scaffold has been identified. Phase 2 SBIR-driven work is envisioned where STING inhibitor ligand chemical series where medicinal and formulation chemistry optimization is performed on the best hit-to-lead chemical series, where in vitro ADME and in vivo PK/PD are performed, and where in vivo proof-of-concept studies are performed in lupus animal models and mouse models of interferonapathies with key lead small molecules. PHS 398/2590 (Rev. 09/04, re-issued 4/2006) Page Continuation Format Page