AeroNeph Tx has discovered multiple novel chemical series that act as STING inhibitors. Their chemistry is unrelated to nucleoside or nucleotide chemistry that are often cytotoxic to human cells; and, indeed, in HTS, a collection of such compounds was cytotoxic. After validation assay steps in human cell-based and cell-free binding assays, STING inhibitor series H has emerged as an important series. The ‘best in class’ STING inhibitor small molecule from family H inhibits all three wild-type STING isoforms and inhibits type 1 interferon production and secretion from THP-1 cells with an estimated IC50 of 2-5 micromolar.
This STING inhibitor and most of the others discovered in our HTS campaign bind to the STING protein target directly. Dr. John Streiff, AeroNeph CSO, has constructed a virtual model of the STING protein structure and has successfully queried the model with mathematical modeling to show where and how the ‘best in class’ STING inhibitor compound H binds within the cGAMP binding pocket (cGAMP is the natural ligand that activates the STING dimer). The binding of compound H in the STING binding pocket (formed by the STING dimer) also has a unique orientation, and John believes that the model has sufficient power to inform medicinal chemistry modification to improve the potency while maintaining the efficacy of inhibition of this lead compound. Compound H also shows the best permeability properties in multiple cell membrane and cell monolayer permeability tests. A provisional patent application is planned for the STING inhibitor compound H series as well as potentially other chemical series that are STING inhibitors.
We are organized to assess brain versus blood pharmacokinetics (PK) in mice and test its efficacy in a trusted mouse model of Parkinson’s disease that involves over-expression of mutant alpha-synuclein protein in the substantia nigra of the brain. Funding for this remains in place from the Michael J. Fox Foundation for AeroNeph Tx. We also await word about successful Phase 2 SBIR renewal of our STING inhibitor grant from the NIH NIAID for AeroNeph Tx. STING inhibitors may be viable therapeutic assets for any and all autoimmune diseases whether they be rare and genetic, tissue-specific, or systemic. Indeed, gain of function mutations in STING cause rare genetic forms of autoimmunity. STING inhibitors may also be therapeutic for Parkinson’s disease, Alzheimer’s disease, and other neuropathies that exhibit autoinflammation.