NODES_INNDIANA_Z88_Clicking Towards a Cure: CIC-39, a Modulator of Store-Operated Calcium Entry in Rare Genetic Myopathies

More than two decades after its conception, click chemistry has proven its significance, culminating in the 2022 Nobel Prize in Chemistry awarded to its pioneers in recognition of its transformative impact on biomedicine. The copper-catalyzed azide-alkyne cycloaddition (CuAAC), the most prominent click reaction, has gained extensive use as a near-perfect ligation strategy in developing therapeutic platforms like PROTACs and ADCs, as highlighted by the recent approval of sacituzumab govitecan for breast cancer treatment. While CuAAC has also been widely employed in early-stage small molecule discovery programs, its clinical translation has faced certain limitations and biases. In this talk, I will present the discovery of CIC-39, identified through a CuAAC-based medicinal chemistry approach as a negative modulator of Store-Operated Calcium Entry (SOCE). SOCE is a calcium signaling pathway that enables cells to detect reduced Ca2+ levels in the endoplasmic reticulum and subsequently promote calcium influx across the plasma membrane. Dysregulation of this pathway has been linked to the pathophysiology of rare muscular disorders, making SOCE a promising therapeutic target for these conditions. CIC-39 has shown efficacy in preclinical models of Tubular Aggregate Myopathy and Duchenne Muscular Dystrophy, leading to its designation as an orphan drug for both conditions. The compound is concluding preclinical development and preparing for the initiation of a Phase I clinical trial through a collaborative effort between academia and industry.