CB-103

CB-103 (CAS No.: 218457-67-1) is a first-in-class, orally active small-molecule inhibitor of the Notch signaling pathway that functions by disrupting the protein–protein interaction within the Notch transcriptional activation complex. Specifically, it binds to the beta-trefoil domain of the transcription factor RBPJ, thereby preventing assembly of the RBPJ–Notch intracellular domain complex and suppressing downstream transcriptional activity. This mechanism results in inhibition of canonical Notch signaling across multiple receptor isoforms and leads to decreased expression of key target genes such as HES1, MYC, and DTX1. In vitro studies demonstrate that CB-103 inhibits ligand-induced Notch signaling at low micromolar concentrations, while in cellular models of T cell acute lymphoblastic leukemia and breast cancer it effectively blocks pathway activation and exhibits antiproliferative effects, including activity in gamma-secretase inhibitor-resistant systems. In vivo, CB-103 has shown the ability to reduce tumor growth and extend survival in xenograft models, consistent with its capacity to induce Notch loss-of-function phenotypes observed in model organisms. As a selective modulator of transcriptional Notch signaling, CB-103 is widely used in oncology research to investigate pathway dependency, resistance mechanisms, and therapeutic targeting strategies, with experimental concentrations and dosing regimens varying according to specific study designs.