JWZ-8-103

JWZ-8-103 is an orally bioavailable small molecule molecular glue designed for the treatment of solid tumors, specifically pancreatic ductal adenocarcinoma (PDAC) and head and neck cancers. Developed as an optimized derivative of the clinical compound PRLX-93936 (an erastin derivative), it functions by binding to the PRYSPRY substrate recognition domain of the TRIM21 E3 ubiquitin ligase. This binding reprograms TRIM21 to act as a molecular glue, recruiting and inducing the degradation of the nuclear pore complex (NPC) protein NUP98. The resulting disruption of the NPC leads to the depletion of short-lived pro-survival mRNAs and triggers rapid, irreversible apoptosis in cancer cells, which exhibit a heightened dependency on nuclear transport compared to normal cells. JWZ-8-103 has demonstrated robust anti-tumor efficacy in KRAS-mutant xenograft models and patient-derived organoids, showing a favorable therapeutic window by preferentially inducing cancer cell death while sparing non-malignant cells.