GZD824 inhibits GCN2 and sensitizes cancer cells to amino acid starvation stress

Yu Kato, Kazuhiro Kunimasa, Mizuki Takahashi, Ayaka Harada, Ikuko Nagasawa, Masanori Osawa, Yoshikazu Sugimoto, Akihiro Tomida

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Eukaryotic initiation factor 2a (eIF2a) kinase general control nonderepressible 2 (GCN2) drives cellular adaptation to amino acid limitation by activating the integrated stress response that induces activating transcription factor 4 (ATF4). Here, we found that a multikinase inhibitor, GZD824, which we identified using a cell-based assay with ATF4 immunostaining, inhibited the GCN2 pathway in cancer cells. Indeed, GZD824 suppressed GCN2 activation, eIF2a phosphorylation, and ATF4 induction during amino acid starvation stress. However, at lower nonsuppressive concentrations, GZD824 paradoxically stimulated eIF2a phosphorylation and ATF4 expression in a GCN2-dependent manner under unstressed conditions. Such dual properties conceivably arose from a direct effect on GCN2, as also observed in a cell-free GCN2 kinase assay and shared by a selective GCN2 inhibitor. Consistent with the GCN2 pathway inhibition, GZD824 sensitized certain cancer cells to amino acid starvation stress similarly to ATF4 knockdown. These results establish GZD824 as a multikinase GCN2 inhibitor and may enhance its utility as a drug under development.

Original languageEnglish
Pages (from-to)669-676
Number of pages8
JournalMolecular Pharmacology
Volume98
Issue number6
DOIs
Publication statusPublished - 2020 Dec

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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