Discovery of Rogocekib (CTX-712): A Potent and Selective CLK Inhibitor for Cancer Treatment

Cdc2-like kinase (CLK) inhibitors represent an innovative class of small molecules designed to modulate RNA splicing patterns, offering a novel avenue for therapeutic intervention in diseases where dysregulated splicing contributes to pathogenesis, particularly in oncology. Here, we describe the discovery of Rogocekib (CTX-712), a promising therapeutic candidate as a CLK inhibitor, which is currently in clinical development. Our medicinal chemistry research involved structure-based drug design-guided scaffold hopping from an initial chemical scaffold and subsequent chemical optimization to generate a novel 1<i>H</i>-imidazo-[4,5-<i>b</i>]-pyridine series. Treatment with CTX-712 reduced the phosphorylation of serine- and arginine-rich proteins in a dose-dependent manner, leading to potent <i>in vitro</i> cell growth suppression and <i>in vivo</i> antitumor activity in lung cancer NCI-H1048 xenograft model. These findings highlight the promise of CTX-712 as a novel CLK inhibitor and its potential as a therapeutic for cancers, particularly those characterized by RNA splicing alterations.