Targeted downmodulation of OXTR and Cx43 in the myometrium by SERTIs as a novel tocolytic strategy

Approximately 10% of US births deliver preterm before 37 weeks of completed gestation. Premature infants are at risk for life-long debilitating morbidities and death, and spontaneous preterm labor explains 50% of preterm births. There are currently no FDA-approved tocolytics, and this research explores the therapeutic potential of 'selective endoplasmic reticulum translocation inhibitors' (SERTIs) for downmodulating contractile-associated proteins in the myometrium. The lead compound in this study, TK047, is an analog of cyclotriazadisulfonamide (CADA), which we found to reduce plasma membrane localization of oxytocin receptor and connexin 43 in human uterine smooth muscle cells, decrease oxytocin-induced calcium influx, and limit Cx43 gap junction channel activity. TK047 imparts strong negative inotropic effects in human and mouse myometrium, and does not exhibit cellular toxicity or affect mouse fetal viability at therapeutic doses. CADA analogs have already been shown to be effective in other disease models, and here they present as a potential first-in-class tocolytic option through the concurrent downmodulation of two contractile-associated proteins essential to parturition.

The online version contains supplementary material available at https://doi.org/10.1186/s44494-026-00005-x.