Small molecules modulating IL-6/STAT3 pathway for potential multiple sclerosis therapy
Chenglong Li, Ph.D., Nicholas Bodor Professor in Drug Discovery
University of Florida, Gainesville, FL 32610, USA
Multiple Sclerosis (MS) is the leading cause of neurologic disability in the United States in young adults after trauma, thus most patients suffer from the effects of MS for most of their adult life. The current MS treatments are partially effective, making it necessary to develop innovative strategies. Interleukin-6 (IL-6), signaling through transcription factor STAT3, shares a central role in multiple pathways of MS pathogenesis and dysregulated IL-6/STAT3 signaling has been shown in MS patients. First, IL-6, signaling through STAT3, induces the generation of highly encephalitogenic IL-17, producing Th17 cells that transfers severe disease in the EAE model of MS. Meanwhile, IL-6 suppresses the generation of inducible T regulatory cells (iTreg), which is critical for dampening pathogenic inflammatory T cell responses. As a result, the Teff/Treg balance is skewed towards excessive T effector responses, favoring the development of autoimmunity. Furthermore, IL-6/STAT3 signaling contributes to the resistance of Teff cells to Treg-mediated suppression in MS patients, which further impairs Teff/Treg balance. Altogether, these studies suggest that the IL-6/STAT3 signaling pathway may serve as an innovative target for reversing pathogenesis in MS patients. In addition, orally available small molecule compounds usually offer improved bioavailability and manufacturing features over commonly used peptide/protein-based drugs. Moreover, therapy adherence is improved when oral agents are used. To this end, we have developed four novel small molecule compounds, MDL-101 and LLM-418 targeting IL-6; LLL-12B and LY-5 targeting STAT3. MDL-101 and LLM-418 bind to the D1 domain of GP130, preventing the IL-6/GP130 interaction during the hexamerization step of IL-6/IL-6R/GP130 signaling complex formation; LLL-12B/LY-5 bind to the SH2 domain of STAT3, preventing STAT3 phosphorylation and dimerization. The compounds significantly inhibit IL-6 induced pSTAT3 and IL-17 production in myelin-specific CD4 T cells; show inhibition of T cell encephalitogenicity in mice adoptive transfer models. Furthermore, the compounds significantly suppress EAE development in chronic EAE model of MS; both acute and relapsing EAE in relapsing-remitting EAE models of MS in vivo. These results establish the basis for future clinical studies using novel pharmacological compounds that target IL-6/STAT3 signaling, with the ultimate goal of treatment of multiple sclerosis.
This work is funded by NIH/NINDS R01NS088437.