Abstract 2385: Evaluation of GCN2 chemical probes: Activity in leukemia

Cellular stress signals activate adaptive signaling pathways of the mammalian integrated stress response (ISR), which converge at the phosporylation of eIF2α. Drug-like chemical inhibitors targeting major ISR kinases have been identified, with the exception of GCN2. We synthesized and evaluated a series of GCN2 inhibitors based on a triazolo[4,5-d]pyrimidine scaffold. Several compounds potently inhibited GCN2 in vitro in orthogonal assays and displayed good selectivity over the related kinases PERK, HRI, and IRE1. The compounds had low solubility at pH 7.4, but sufficient permeability to inhibit phosporylation of eIF2α in HEK293T cells with an IC 50 Citation Format: Lea Lough, Dan Sherman, Eric Ni, Palaniraja Thandapani, Ioannis Aifantis, Timothy Cardozo. Evaluation of GCN2 chemical probes: Activity in leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2385.