GSI-I

GSI-I (Z-LLNle-CHO) is a peptide aldehyde that functions as a potent inhibitor of both the gamma-secretase complex and the 26S proteasome. Originally identified as a gamma-secretase inhibitor (GSI) to block the Notch signaling pathway by preventing the cleavage of the Notch intracellular domain (NICD), it is widely recognized in oncology research for its significant off-target inhibition of the proteasome. This dual mechanism of action leads to the accumulation of ubiquitinated proteins, induction of endoplasmic reticulum stress, and cell cycle arrest in the G2/M and S phases. In preclinical models of ovarian cancer, GSI-I has demonstrated the ability to synergize with Hedgehog pathway inhibitors, such as sonidegib (LDE225), through a Notch-independent mechanism involving proteasome inhibition. It is primarily utilized as a research tool to investigate the crosstalk between stem cell signaling pathways and chemoresistance mechanisms.

Other names

Gamma-Secretase Inhibitor IZ-L-Leu-L-Leu-L-norleucinal