Immune Modulatory Small Molecules for the Treatment of Sepsis and Autoimmune Diseases
SUMMARY
- Tumor necrosis factor alpha (TNFα) is an important cytokine that activates cell death programs in response to acute inflammation. TNFα inhibitors are currently used to treat a multitude of autoimmune diseases, but problematically they also inhibit beneficial TNFα functions such as combating infections and cancer surveillance. Therefore, inhibitors that selectively target TNFα-induced cytotoxicity while preserving desirable TNFα-mediated functions are needed.
- The inventors discovered that cytotoxic and non-cytotoxic doses of TNFα utilize different mechanisms to induce apoptosis. Induction of cytotoxic effects involves re-distribution of the BCL-2 family protein BAD from the cytoskeleton to the cytosol.
- The invention is a group of novel small-molecule Src kinase inhibitors that block BAD re-distribution from the cytoskeleton to the cytosol and therefore selectively inhibit TNFα-induced cytotoxicity without inhibiting TNFα beneficial effects. These small molecules have potential for use in the treatment of autoimmune diseases as well as sepsis.
- In in vivo experiments, compound ZG-5129 reduced the mortality rate of mice in polymicrobial infection-induced severe sepsis models when administered at doses as low as 2.5mg/kg body weight (p<0.01).
FIGURE
Kaplan-Meier survival curve for a mouse model of polymicrobial infection treated with a novel small molecule Src inhibitor.
ADVANTAGES
ADVANTAGES
- Selectively inhibits TNFα cytotoxicity
- Retains desirable TNFα-mediated pathways
- Applicable in multiple disease indications
APPLICATIONS
- Prevention of organ damage in sepsis
- Treatment of transplant organ graft rejection
- Treatment of Alzheimers and associated neurological disorders
- Inflammatory disease treatment
PUBLICATIONS
- US: 16/329,499
- PoC for several diseases including: Sepsis, Alzheimers, Organ graft rejection