35G8

35G8 (also known as RGNCY-0084) is a blood-brain barrier-permeable, small-molecule inhibitor of protein disulfide isomerase (PDI) family proteins, specifically targeting PDIA1 and PDIA4. Originally discovered through a phenotypic screening campaign of cytotoxic compounds at the University of Michigan, 35G8 has demonstrated potent anti-tumor activity in preclinical models of glioblastoma and inflammatory breast cancer (IBC) brain metastasis. Mechanistically, 35G8 binds to the catalytic active sites of PDI, disrupting protein folding and inducing endoplasmic reticulum (ER) stress, the unfolded protein response (UPR), and cell death via autophagy and ferroptosis. In inflammatory breast cancer models, 35G8 suppresses brain metastasis by targeting the sEcad-PDIA4 axis.

Other names

1,3,6-trimethylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione1,3,6-trimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione