2) PERK pathway facilitated the protein secretion, amino acid metabolism, and stress response to promote cell survival via phosphorylating eIF2α level and strengthening ATF4 expression; Nevertheless, the prolonged activating of the PERK pathway could up-regulate CHOP, GADD34, and other pro-apoptotic factors to further aggravates cell injury. 3) IRE1 and ATF6 pathways enhanced various gene transcription associated with protein folding, secreting, EARD, and ERQC to prompt cell protein homeostasis micro-environment; However, sustained IRE1 and/or ATF6 activity could prompt cell survival toward apoptosis via the pro-apoptotic pathway, inflammation, and other patterns.

The structural analogs KZR-261 and KZR-834 were identified through a medicinal chemistry campaign and found to have broad in vitro anti-tumor activity and efficacy in mouse xenograft models. Flow cytometric analysis of PBMCs also showed a significant reduction in surface expression of those proteins in multiple cell populations.Our results highlight quantitative proteomic profiling as a valuable tool towards elucidation of the mechanism of pleiotropically-acting molecules. By assessing global proteomic changes in non-transformed cells, pharmacodynamic markers were identified that will be employed in the Phase 1 trial of KZR-261 in solid tumors.