NADI-351

NADI-351 is an orally available, potent, and selective small molecule inhibitor of the Notch1 transcriptional complex. It operates by disrupting Notch1-mediated transcription, thereby selectively ablating cancer stem cell populations that sustain tumor growth and resistance to therapies. Preclinical studies demonstrate that NADI-351 robustly inhibits tumor growth across various cancer models, including esophageal adenocarcinoma and triple-negative breast cancer, without causing gastrointestinal toxicity characteristic of less selective Notch pathway inhibitors. By preventing the formation of the Notch1 transcriptional complex (specifically by blocking Notch1ICD and MAML1 interactions with DNA via CSL), NADI-351 downregulates Notch target gene expression, induces cell cycle arrest in S-phase, and promotes apoptosis in cancer stem cell populations. The compound is being developed as a targeted cancer therapy, with an initial focus on solid tumors that demonstrate Notch1 pathway dependency[1][3][5][7][8][9][10].