Discovery of Novel Therapeutic Target STMN1 and Drug Investigation in Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP), an autosomal dominant disorder that predisposes to colorectal cancer, remains an area of unmet clinical need. This study aimed to develop a novel STMN1-targeting therapy for FAP. Using patient-derived organoids from seven FAP families and RNA sequencing, we identified significant STMN1 upregulation in FAP tissues, correlating with poor prognosis. Through drug repurposing and pharmacophore-based virtual screening of the DrugBank database, we optimized the menadione scaffold to develop novel small-molecule inhibitors. JYL-6 emerged as a leading compound in primary screens using FAP organoids. In Apcmin/+ mice, JYL-6 potently suppressed STMN1 expression and phosphorylation, reduced intestinal polyp number and burden, extended survival, and demonstrated a favorable systemic safety profile. Our results nominate STMN1 as a promising therapeutic target in FAP and highlight JYL-6 as a candidate with substantial translational promise, offering a new strategic direction for FAP treatment.