A STAT3 inhibitor ameliorates CNS autoimmunity by restoring Teff:Treg Balance

Abstract

Reestablishing an appropriate balance between T effector cells (Teff) and Tregs is essential for correcting autoimmunity. Multiple sclerosis (MS) is an immune-mediated chronic CNS disease characterized by neuroinflammation, demyelination, and neuronal degeneration, in which the Teff:Treg balance is skewed toward pathogenic Teffs Th1 and Th17 cells. STAT3 is a key regulator of Teff:Treg balance. Using the structure-based design, we have developed a potentially novel small-molecule prodrug LLL12b that specifically inhibits STAT3 and suppresses Th17 differentiation and expansion. Moreover, LLL12b regulates the fate decision between Th17 and Tregs in an inflammatory environment, shifting Th17:Treg balance toward Tregs and favoring the resolution of inflammation. Therapeutic administration of LLL12b after disease onset significantly suppresses disease progression in adoptively transferred, chronic, and relapsing-remitting experimental autoimmune encephalomyelitis. Disease relapses were also significantly suppressed by LLL12b given during the remission phase. Additionally, LLL12b shifts Th17:Treg balance of CD4 + T cells from MS patients toward Tregs and increases Teff sensitivity to Treg-mediated suppression. These data suggest that selective inhibition of STAT3 by the small molecule LLL12b recalibrates the effector and regulatory arms of CD4 + T responses, representing a potentially clinically translatable therapeutic strategy for MS.

Transcriptional regulatory networks of circulating immune cells in type 1 diabetes: A community knowledgebase

“…Moreover, NR4A1 has been identified as a potential therapeutic target in central nervous system autoimmune-based inflammation ( Rothe et al., 2017 ). ET1DIE transcription factor nodes included STAT3, a well-characterized driver of numerous autoimmune conditions ( Aqel et al., 2021 ) and as previously noted, was also identified as a ET1DRE node. They also included RELA, a subunit of the well-known pro-inflammatory mediator NFκB, which has known roles as a driver of autoimmune disorders ( Sun et al., 2013 ).…”

A novel small molecule LLL12B inhibits STAT3 signaling and sensitizes ovarian cancer cell to paclitaxel and cisplatin

“…LLL12B has one of the smallest molecular weights (374 dalton) compared to other STAT3 inhibitors. In addition, our in vivo pharmacokinetic studies in rats indicated that LLL12B is orally bioavailable (38.0%) and stable in the plasma, producing drug levels 5-fold better compared to LLL12 [20]. These results support that LLL12B is a superior drug relative to LLL12 to target STAT3 in ovarian cancer cells.…”

“…The small molecule LLL12B, a novel STAT3 inhibitor, was synthesized at University of Florida College of Pharmacy (Chenglong Li) [20]. LLL12B powder was dissolved in sterile dimethyl sulfoxide (DMSO) to make a 20 mM stock solution and stored at -20˚C.…”

LLL12B, a Novel Small-Molecule STAT3 Inhibitor, Induces Apoptosis and Suppresses Cell Migration and Tumor Growth in Triple-Negative Breast Cancer Cells

“…We identified that LLL12B, a prodrug of LLL12, is activated by the tumor-associated plasmin through the hydrolytic cleavage of the carbamate ester bond to release LLL12 [ 26 ]. It directly binds to the pTyr705 binding site of STAT3 with improved in vivo pharmacokinetic properties relative to the parent drug LLL12, which supports that it has superior and selective inhibition of STAT3 [ 25 , 27 , 28 ]. In this study, we tested LLL12B in TNBC cells and the results showed that targeting STAT3 with LLL12B induced apoptosis and suppressed colony formation, migration, and tumor growth in TNBC cells.…”