Targeted Therapy to Inhibit cGAS Stimulated Type I IFN Production

Focus: 

To synthesize and test new drugs for systemic lupus erythematosus (SLE)

Anticipated Impact: 

Improved treatment of lupus and better quality of life for affected individuals

Abstract: 

Systemic lupus erythematosus (SLE) is an autoimmune disorder with significant morbidity and mortality. Current therapies have limited efficacy and are associated with serious and sometimes fatal side effects. Dr. Elkon and his team have found that the recently described cyclic GAMP synthase (cGAS) molecular pathway may be activated in the disease, and they have designed three compounds that are predicted to inhibit cGAS activity. LSDF funding will support synthesis and laboratory testing of those compounds, as well as in vivo testing of the most promising candidate. If successful, formation of a new company to commercialize this compound as a new treatment for lupus is anticipated. 

Lupus Management

Grant Update

Principal Investigator:
Keith Elkon
Grantee Organization:
University of Washington
Grant Title:
Targeted Therapy to Inhibit cGAS stimulated Type I IFN Production
Grant Cohort and Year:
2014 Proof of Concept (03)
Grant Period:
11/01/2014 - 10/31/2016 (Completed)
Grant Amount:
$264,950
There are several diseases that are associated with the overproduction of an inflammatory pathway driven by the cytokines belonging to the Type I interferon (T I IFN) pathway. These diseases include systemic lupus erythematosus (SLE) as well as a group of potentially fatal childhood diseases called “interferonopathies". Amongst the prominent pathways that can stimulate TI IFN is one called cGAS/STING. Our LSDF project proposed to synthesize a drug that is designed to block the cGAS/STING inflammatory pathway. In the first phase of this project, we synthesized 3 drugs that had similar structures to currently existing antimalarial drugs. Computer modeling predicted higher efficacy of binding to cGAS and interference with activation by the DNA ligand. In practice, we identified one of these drugs, referred to as X6, that had a comparable IC50 to the most potent antimalarial drugs in terms of inhibition of TI IFN production but had much lower (~10-fold) toxicity. During the past 6 months we have analyzed our test results and found that X6 significantly achieved its goals.

Impact in Washington

Location of LSDF Grantee
Locations of Collaborations/Areas of Impact
Seattle

Legislative Districts:
11, 34, 36, 37, 43, 46

Health Impacts

Lupus Management