NODES_INNDIANA_Z104_SO4CE Modulation in Duchenne Muscular Dystrophy and Multiple Sclerosis: Discovery of Preclinical Candidate CIC-39 via a Click Chemistry Approach

Store-Operated Calcium Entry (SOCE) is a critical calcium signaling mechanism that detects Ca2+ depletion in the endo/sarcoplasmic reticulum and triggers extracellular Ca2+ influx across the plasma membrane. Dysregulation of SOCE has been increasingly implicated in calcium homeostasis impairment and in the pathogenesis of several diseases, including rare muscular disorders, such as Duchenne muscular dystrophy (DMD), and autoimmune conditions, like multiple sclerosis (MS). These findings highlight SOCE as a valuable but underexploited pharmacological target.In DMD, the most prevalent inherited pediatric myopathy, dystrophin gene mutations lead to aberrant SOCE activation, contributing to muscle degeneration and premature death. Similarly, in MS, a neuroinflammatory demyelinating disease of the central nervous system, SOCE overactivation has been linked to lymphocyte activation and excessive pro-inflammatory cytokine release.In this contribution, I will present the discovery and preclinical development of CIC-39 a selective SOCE modulator identified via a copper-catalyzed azide–alkyne cycloaddition (CuAAC)-driven medicinal chemistry strategy. CIC-39 has shown robust efficacy in preclinical models of both DMD and MS. In DMD, it significantly reduces serum creatine kinase levels and muscle cell death in vivo in mdx mouse model, while also modulating inflammatory and fibrotic biomarkers in patient-derived cells. In MS, CIC-39 attenuates disease progression and clinical severity in the experimental autoimmune encephalomyelitis model and suppresses Th1/Th17 cytokine expression in patient-derived lymphocytes. Our lead compound is completing preclinical development and is on track to enter a Phase I clinical trial through an academic–ChemiCare S.r.l. partnership.