| Title: |
A novel potent and selective GCN2 inhibitor, APL-4098, has anti-leukemic activity through dysregulation of mitochondrial function |
| Authors: |
Román-Trufero, Monica; Whitlock, Gavin; Seydoux, Claire; Blighe, Kevin; Perfler, Bianca; Zebisch, Armin; Butt, Richard; Fuchter, Matthew J; Auner, Holger W; Clemo, Nadine |
| Publication Year: |
2026 |
| Collection: |
Université de Lausanne (UNIL): Serval - Serveur académique lausannois |
| Description: |
GCN2, one of the four kinases that activate the Integrated Stress Response to maintain proteostasis, has been shown to support cancer cell growth and survival in multiple preclinical cancer models. Acute myeloid leukemia (AML) is an aggressive hematological malignancy with dismal prognosis and high relapse rates that is marked by a dependency on finely tuned proteostasis. Here, we investigate the anti-leukemic potential of a new small-molecule GCN2 inhibitor, APL-4098. selectivity and potency of APL-4098 were assessed using biochemical and cell-based assays. Anti-leukemic effects were evaluated ex vivo in primary patient-derived AML and in vivo using cell line-derived (CDX) and patient-derived (PDX) xenograft models. Synergy of APL-4098 and venetoclax was examined in the PDX. RNA sequencing and metabolic assays were used to explore APL-4098 mechanism of action. APL-4098 exhibited nanomolar-range potency against and high selectivity for GCN2. APL-4098 showed strong anti-proliferative activity ex vivo across two independent cohorts of primary AML patient cells, including cytotoxic effects on the leukemia stem cells (LSCs) and in vivo, achieving 98% tumor growth inhibition in an AML CDX. In a PDX, APL-4098 preferentially depleted the LSC-enriched compartment and, in combination with venetoclax, reduced leukemia burden by over 98%. Transcriptomic and metabolic analyses revealed APL-4098 compromises mitochondrial function and elicits the mitochondrial unfolded protein response. APL-4098 is a novel, potent and selective GCN2 inhibitor with strong preclinical efficacy against AML cells, including LSCs. Our findings support APL-4098 as a promising candidate for AML treatment. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
1078-0432 |
| Relation: |
Clinical Cancer Research; https://iris.unil.ch/handle/iris/280060 |
| DOI: |
10.1158/1078-0432.CCR-25-1444 |
| Availability: |
https://iris.unil.ch/handle/iris/280060; https://doi.org/10.1158/1078-0432.CCR-25-1444 |
| Accession Number: |
edsbas.E39878B9 |
| Database: |
BASE |