Summary We are developing small molecule antagonists for cyclic GAMP synthase (cGAS) to identify a candidate drug molecule for lupus. Systemic lupus erythematosus (SLE), or simply lupus, is the second most common autoimmune disease next to rheumatoid arthritis; there are at least 300,000 patients in the U.S. alone and well over a million globally. The unmet medical need is enormous: lupus patients suffer from a 67% increase in mortality rate with damage to major organs in 50% of cases; e.g., heart, lung, kidneys, and brain; lupus was the 5th leading cause of death among young African American and Hispanic women in the U.S. from 2011-2015. There are no curative treatments for lupus, and only one drug (Benlysta) has been approved in the last 50 years. Lupus pathology is driven by type I interferons (IFNs), and the immune sensor, cyclic GAMP synthase (cGAS), is the trigger for type I IFN induction. DNA from dying cells binds to catalytically inactive cGAS to form an activated complex, triggering production of a unique cyclic nucleotide second messenger, cyclic GAMP (cGAMP). cGAMP binds to the STING protein to induce expression of type I IFNs, with autocrine and paracrine effects that lead to activation of T- and B-cells and auto-antibody production, precipitating a vicious cycle of cell death and autoimmunity. Using an innovative HTS assay developed under a separate SBIR, we discovered two promising cGAS antagonist chemotypes (40783 and 50101) that function via distinct mechanisms and have made substantial progress on increasing their biochemical and cellular potency while maintaining ADME properties predictive of good oral bioavailability. Our structural data indicate that the 40783 chemotype has allosteric binding properties and may stabilize an inactive cGAS conformation, properties which we will leverage in Phase II to develop a highly selective lead molecule with a long residence time. The 50101 chemotype appears to bind specifically to a hypersensitized cGAS-Mn-DNA complex, which could lead to an improved therapeutic window. In Phase II we propose to: 1) further optimize the potency, selectivity and ADME properties of the two chemotypes and 2) test their efficacy in an innovative model for UV-induced photosensitivity that replicates key aspects of SLE pathology and aligns closely with our clinical strategy. The animal efficacy studies will be performed in collaboration with Keith Elkon, Head of Rheumatology at University of Washington, Seattle, who developed the mouse photosensitivity model and has pioneered research on the involvement of the cGAS/STING pathway in lupus. Most investigational lupus drugs target the downstream effects of type I IFNs, a strategy that is akin to plugging holes in a sinking ship. The development of drugs that target cGAS, the upstream molecular trigger for nucleic-acid driven type I IFN production could revolutionize the treatment of lupus along with a growing list of cGAS- driven autoimmune and inflammatory con...