NODES_Inndiana_Z68_Discovery and development of SOCE modulator CIC-39 and its prodrugs as a therapy for Tubular Aggregate Myopathy and Duchenne Muscular Dystrophy

"Store-Operated Calcium Entry (SOCE) is a Ca2+ signal pathway that consists in the ability of cells to sense a decrease in endoplasmic reticulum luminal Ca2+ and induce Ca2+ entry across the plasma membrane. It relies on two key players: STIM proteins and ORAI channels. Lines of evidence reported Ca2+ homeostasis dysregulation and a crucial role of SOCE mechanism in the pathophysiology of rare muscular disorders (e.g., myopathies and dystrophies) as well as autoimmune diseases, thus making SOCE as a novel therapeutic target in these conditions. 
In this perspective, a copper-catalyzed azide-alkyne cycloaddition-based medicinal chemistry campaign led to the discovery of CIC-39, a negative modulator of SOCE, as the lead compound endowed with high selectivity over other Ca2+-permeable channels, a good pharmacokinetic profile and an excellent safety profile. Based on its efficacy in models of Tubular Aggregate Myopathy (TAM) and Duchenne Muscular Dystrophy (DMD), CIC-39 has received two orphan designations and is now being preclinically developed through a collaborative project between academia and industry. 
So far, the in vivo efficacy of CIC-39 has been demonstrated in adult mice using intraperitoneal minipumps. However, this delivery strategy is not feasible in younger animals, where early treatment is crucial due to the genetic nature of TAM and DMD. To address this issue, we developed a library of prodrugs as injectable oil depot formulations for SC administration. We identified prodrug 3 as the best compound in terms of hydrolytic stability in mouse plasma and log P value, as well as solubility in the selected oil-based vehicle. In view of the in vivo testing, we have planned a PK study of compound 3 in 2-week-old wild-type mice."